bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Paracrine Placental Growth Factor Signaling in Response to Ionizing Radiation Is p53-Dependent and Contributes to Radioresistance
Authors: Kazimova Tamara , Tschanz Fabienne , Sharma Ashish , Telarovic Irma , Wachtel Marco , Pedot Gloria , Schäfer Beat , Pruschy Martin
Published: April 2023

Abstract
Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated growth factor, which is secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis and radiosensitivity. Secretion and expression of PlGF was induced in multiple tumor cell lines (medulloblastoma, colon and lung adenocarcinoma) in response to irradiation in a dose- and time-dependent manner. Early upregulation of PlGF expression and secretion in response to irradiation was primarily observed in p53 wild-type tumor cells, whereas tumor cells with mutated p53 only showed a minimal or delayed response. Mechanistic investigations with genetic and pharmacologic targeting of p53 corroborated regulation of PlGF by the tumor suppressor p53 in response to irradiation under normoxic and hypoxic conditions, but with so far unresolved mechanisms relevant for its minimal and delayed expression in tumor cells with a p53-mutated genetic background. Probing a paracrine role of IR-induced PlGF secretion in vitro, migration of endothelial cells was specifically increased towards irradiated PlGF wild type but not towards irradiated PlGF-knockout (PIGF-ko) medulloblastoma cells. Tumors derived from these PlGF-ko cells displayed a reduced growth rate, but similar tumor vasculature formation as in their wild-type counterparts. Interestingly though, high-dose irradiation strongly reduced microvessel density with a concomitant high rate of complete tumor regression only in the PlGF-ko tumors.
Implications:
Our study shows a strong paracrine vasculature-protective role of PlGF as part of a p53-regulated IR-induced resistance mechanism and suggest PlGF as a promising target for a combined treatment modality with RT.
Data from Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in ApcS580/+; KrasG12D/+ Mice
Authors: Han Huajun , Davidson Laurie A. , Hensel Martha , Yoon Grace , Landrock Kerstin , Allred Clinton , Jayaraman Arul , Ivanov Ivan , Safe Stephen H. , Chapkin Robert S.
Published: April 2023

Abstract
The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of “cooperation response genes” to modulate the function of cancer “driver” genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell–targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis.
Implications:
Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.
Data from Gene Body Methylation of the Lymphocyte-Specific Gene CARD11 Results in Its Overexpression and Regulates Cancer mTOR Signaling
Authors: McGuire Michael H. , Dasari Santosh K. , Yao Hui , Wen Yunfei , Mangala Lingegowda S. , Bayraktar Emine , Ma Wencai , Ivan Cristina , Shoshan Einav , Wu Sherry Y. , Jonasch Eric , Bar-Eli Menashe , Wang Jing , Baggerly Keith A. , Sood Anil K.
Published: April 2023

Abstract
Investigations into the function of nonpromoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated nonpromoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we examined 32 tumor types and identified 57 tumor suppressors and oncogenes out of 260 genes exhibiting a correlation of > 0.5 between gene body methylation and gene expression in at least one tumor type. The lymphocyte-specific gene CARD11 exhibits robust association between gene body methylation and expression across 19 of 32 tumor types examined. It is significantly overexpressed in kidney renal cell carcinoma (KIRC) and lung adenocarcinoma (LUAD) tumor tissues in comparison with respective control samples; and is significantly associated with lower overall survival in KIRC. Contrary to its canonical function in lymphocyte NFκB activation, CARD11 activates the mTOR pathway in KIRC and LUAD, resulting in suppressed autophagy. Furthermore, demethylation of a CpG island within the gene body of CARD11 decreases gene expression. Collectively, our study highlights how DNA methylation outside the promoter region can impact tumor progression.
Implications:
Our study describes a novel regulatory role of gene body DNA methylation–dependent CARD11 expression on mTOR signaling and its impact on tumor progression.
Data from Exosomal Delivery of FTO Confers Gefitinib Resistance to Recipient Cells through ABCC10 Regulation in an m6A-dependent Manner
Authors: Xiao Peng , Liu Yu-kang , Han Wei , Hu Yan , Zhang Bo-you , Liu Wen-liang
Published: April 2023

Abstract
Gefitinib is suitable for the treatment of locally advanced or metastatic non–small cell lung cancer. However, the development of acquired resistance limits its long-term efficacy in regardless of significant clinical benefit to patients. Therefore, to elucidate the mechanism of gefitinib resistance in addition to target gene mutation may greatly increase its clinical efficacy. It was found first that N6-methyladenosine RNA demethylase FTO was significantly enriched in serum exosomes of gefitinib-resistant (GR) patients compared with that of gefitinib-sensitive (GS) patients through exosomal RNA sequencing. Meanwhile, the average m6A proportion in GR patients was significantly lower when compared with that in GS patients. Besides, GR cell–derived exosome internalization attenuated the total m6A abundance and gefitinib sensitivity of PC9 cells. Not only FTO knockdown enhanced the gefitinib sensitivity of GR cells but also FTO reduction in donor exosomes alleviated the acquired resistance of recipient PC9 cells. GR cell–derived exosomal-FTO promoted ABCC10 of recipient cells in a m6A-dependent manner. FTO/YTHDF2/ABCC10 axis played a role in intercellular transmission of GR cell–derived exosome-mediated gefitinib resistance both in vitro and in vivo. In general, this research showed that m6A modification was involved in the decrease of gefitinib sensitivity. GR cell–derived exosomes could decrease gefitinib sensitivity of recipient cells in exosomal delivery of FTO-dependent manner. FTO/YTHDF2/ABCC10 axis played a role in intercellular transmission of GR cell–derived exosome-mediated gefitinib resistance.
Implications:
Our results elucidated another potential molecular mechanism of gefitinib resistance in non–small cell lung cancer besides secondary EGFR mutations.
Data from Fatty Acid Oxidation Is an Adaptive Survival Pathway Induced in Prostate Tumors by HSP90 Inhibition
Authors: Nassar Zeyad D. , Mah Chui Yan , Centenera Margaret M. , Irani Swati , Sadowski Martin C. , Scott Julia S. , Nguyen Elizabeth V. , Nagarajan Shilpa R. , Moldovan Max , Lynn David J. , Daly Roger J. , Hoy Andrew J. , Butler Lisa M.
Published: April 2023

Abstract
HSP90 is a molecular chaperone required for stabilization and activation of hundreds of client proteins, including many known oncoproteins. AUY922 (luminespib), a new-generation HSP90 inhibitor, exhibits potent preclinical efficacy against several cancer types including prostate cancer. However, clinical use of HSP90 inhibitors for prostate cancer has been limited by toxicity and treatment resistance. Here, we aimed to design an effective combinatorial therapeutic regimen that utilizes subtoxic doses of AUY922, by identifying potential survival pathways induced by AUY922 in clinical prostate tumors. We conducted a proteomic analysis of 30 patient-derived explants (PDE) cultured in the absence and presence of AUY922, using quantitative mass spectrometry. AUY922 significantly increased the abundance of proteins involved in oxidative phosphorylation and fatty acid metabolism in the PDEs. Consistent with these findings, AUY922-treated prostate cancer cell lines exhibited increased mitochondrial mass and activated fatty acid metabolism processes. We hypothesized that activation of fatty acid oxidation is a potential adaptive response to AUY922 treatment and that cotargeting this process will sensitize prostate cancer cells to HSP90 inhibition. Combination treatment of AUY922 with a clinical inhibitor of fatty acid oxidation, perhexiline, synergistically decreased viability of several prostate cancer cell lines, and had significant efficacy in PDEs. The novel drug combination treatment induced cell-cycle arrest and apoptosis, and attenuated the heat shock response, a known mediator of HSP90 treatment resistance. This combination warrants further preclinical and clinical investigation as a novel strategy to overcome resistance to HSP90 inhibition.
Implications:
Metabolic pathways induced in tumor cells by therapeutic agents may be critical, but targetable, mediators of treatment resistance.
Data from ADGRL4/ELTD1 Expression in Breast Cancer Cells Induces Vascular Normalization and Immune Suppression
Authors: Sheldon Helen , Bridges Esther , Silva Ildefonso , Masiero Massimo , Favara David M. , Wang Dian , Leek Russell , Snell Cameron , Roxanis Ioannis , Kreuzer Mira , Gileadi Uzi , Buffa Francesca M. , Banham Alison , Harris Adrian L.
Published: April 2023

Abstract
ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumor types and this correlates with a good prognosis. Expression has also been reported in some tumor cells with high expression correlating with a good prognosis in hepatocellular carcinoma (HCC) and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumors stain positively for ELTD1, with 9% having high expression that correlates with improved relapse-free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumors expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumors had larger and better perfused vessels and tumor–endothelial cell interaction led to the release of proangiogenic and immune-modulating factors. M2-like macrophages increased in the stroma along with expression of programmed death-ligand 1 (PD-L1) on tumor and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1-regulated tumor growth in the presence of an NY-ESO-1–specific immune response. Eltd1-positive tumors also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumors. ELTD1 may be useful as a selection marker for such therapies.
Implications:
ELTD1 expression in mouse breast tumors creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.
Data from Crucial Functions of the JMJD1/KDM3 Epigenetic Regulators in Cancer
Authors: Sui Yuan , Gu Ruicai , Janknecht Ralf
Published: April 2023

Abstract
Epigenetic changes are one underlying cause for cancer development and often due to dysregulation of enzymes modifying DNA or histones. Most Jumonji C domain-containing (JMJD) proteins are histone lysine demethylases (KDM) and therefore epigenetic regulators. One JMJD subfamily consists of JMJD1A/KDM3A, JMJD1B/KDM3B, and JMJD1C/KDM3C that are roughly 50% identical at the amino acid level. All three JMJD1 proteins are capable of removing dimethyl and monomethyl marks from lysine 9 on histone H3 and might also demethylate histone H4 on arginine 3 and nonhistone proteins. Analysis of knockout mice revealed critical roles for JMJD1 proteins in fertility, obesity, metabolic syndrome, and heart disease. Importantly, a plethora of studies demonstrated that especially JMJD1A and JMJD1C are overexpressed in various tumors, stimulate cancer cell proliferation and invasion, and facilitate efficient tumor growth. However, JMJD1A may also inhibit the formation of germ cell tumors. Likewise, JMJD1B appears to be a tumor suppressor in acute myeloid leukemia, but a tumor promoter in other cancers. Notably, by reducing methylation levels on histone H3 lysine 9, JMJD1 proteins can profoundly alter the transcriptome and thereby affect tumorigenesis, including through upregulating oncogenes such as CCND1, JUN, and MYC. This epigenetic activity of JMJD1 proteins is sensitive to heavy metals, oncometabolites, oxygen, and reactive oxygen species, whose levels are frequently altered within cancer cells. In conclusion, inhibition of JMJD1 enzymatic activity through small molecules is predicted to be beneficial in many different cancers, but not in the few malignancies where JMJD1 proteins apparently exert tumor-suppressive functions.
Data from Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7–APEH–Proteasome Axis in High-grade Serous Ovarian Carcinoma
Authors: Tangri Apoorva , Lighty Kinzie , Loganathan Jagadish , Mesmar Fahmi , Podicheti Ram , Zhang Chi , Iwanicki Marcin , Drapkin Ronny , Nakshatri Harikrishna , Mitra Sumegha
Published: April 2023

Abstract
High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the in vivo metastatic growth of ovarian cancer xenografts. Transcriptional profiling of UCHL1-silenced HGSOC cells revealed downregulation of genes implicated with proteasome activity along with upregulation of endoplasmic reticulum stress–induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH), upon silencing of UCHL1, resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1-silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7–APEH–proteasome axis.
Implications:
This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC and recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors.
Data from Monoallelic IDH1 R132H Mutation Mediates Glioma Cell Response to Anticancer Therapies via Induction of Senescence
Authors: Zhan Daqian , Ma Ding , Wei Shuang , Lal Bachchu , Fu Yi , Eberhart Charles , Laterra John , Ying Mingyao , Li Yunqing , Meeker Alan , Lopez-Bertoni Hernando , Xia Shuli
Published: April 2023

Abstract
Heterozygous isocitrate dehydrogenase (IDH) R132H mutation (IDH1R132H/WT) is an early event during gliomagenesis. Clinically, patients with glioma carrying mutant IDH1 respond better to antitumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1R132H/WT in glioma cells significantly enhanced gliomas cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1R132H/WT-induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1R132H/WT transformed nonneoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these precancerous cells underwent senescence-like phenotypic changes, including flat and enlarged-cell morphology, increased senescence marker expression, decreased cell proliferation, and cell-cycle arrest at the G2–M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNAdamage response (DDR) pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non–cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of proinflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill precancerous cells and senescent tumor cells following antitumor therapies.
Implications:
The mechanisms by which IDH1 mutations contribute to gliomagenesis and therapeutic responses remain incompletely characterized; this work reveals senescence as a novel mechanism of IDH-mutant–mediated biological impact and describes new therapeutic opportunities concerning IDH1-mutant gliomas.
Data from R-Loop–Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin
Authors: Safari Maryam , Litman Thomas , Robey Robert W. , Aguilera Andrés , Chakraborty Arup R. , Reinhold William C. , Basseville Agnes , Petrukhin Lubov , Scotto Luigi , O'Connor Owen A. , Pommier Yves , Fojo Antonio T. , Bates Susan E.
Published: April 2023

Abstract
Histone deacetylase inhibitors (HDACi) induce hyperacetylation of histones by blocking HDAC catalytic sites. Despite regulatory approvals in hematological malignancies, limited solid tumor clinical activity has constrained their potential, arguing for better understanding of mechanisms of action (MOA). Multiple activities of HDACis have been demonstrated, dependent on cell context, beyond the canonical induction of gene expression. Here, using a clinically relevant exposure duration, we established DNA damage as the dominant signature using the NCI-60 cell line database and then focused on the mechanism by which hyperacetylation induces DNA damage. We identified accumulation of DNA–RNA hybrids (R-loops) following romidepsin-induced histone hyperacetylation, with single-stranded DNA (ssDNA) breaks detected by single-cell electrophoresis. Our data suggest that transcription-coupled base excision repair (BER) is involved in resolving ssDNA breaks that, when overwhelmed, evolve to lethal dsDNA breaks. We show that inhibition of BER proteins such as PARP will increase dsDNA breaks in this context. These studies establish accumulation of R-loops as a consequence of romidepsin-mediated histone hyperacetylation. We believe that the insights provided will inform design of more effective combination therapy with HDACis for treatment of solid tumors.
Implications:
Key HDAC inhibitor mechanisms of action remain unknown; we identify accumulation of DNA–RNA hybrids (R-loops) due to chromatin hyperacetylation that provokes single-stranded DNA damage as a first step toward cell death.
Data from LINC00239 Interacts with C-Myc Promoter-Binding Protein-1 (MBP-1) to Promote Expression of C-Myc in Esophageal Squamous Cell Carcinoma
Authors: Liang Xiaoliang , Lu Juntao , Wu Zheng , Guo Yanli , Shen Supeng , Liang Jia , Dong Zhiming , Guo Wei
Published: April 2023

Abstract
Increasing evidence demonstrates that long non-coding RNAs (lncRNA) play a vital role in the progression of tumors, containing esophageal squamous cell carcinoma (ESCC). LINC00239 was reported as an oncogene in diverse kinds of cancers, whereas its specific role is still unclear in ESCC. In this study, we detected the expression and functional role of LINC00239 in ESCC specimens and cells, and investigated the molecular mechanisms of it. LINC00239 was highly expressed in ESCC tissues and cells, and was related to poor prognosis of patients with ESCC. The proliferation, metastasis, and invasion ability as well as epithelial–mesenchymal transition (EMT) process were all enhanced in LINC00239-overexpressed ESCC cells. LINC00239 was upregulated in TGF-β1–treated ESCC cells. Furthermore, LINC00239 was found to bind directly to the transcription factor c-Myc promoter–binding protein-1 (MBP-1). MBP-1 was detected to inhibit the transcription of c-Myc in ESCC. Moreover, LINC00239 could activate c-Myc transcription through influencing MBP-1–binding ability to c-Myc promoter. These data suggest that LINC00239 may act as an oncogene to promote the transcription of c-Myc by competitively combining with MBP-1 in ESCC, and may serve as a potential target for antitumor therapy in ESCC.
Implications:
LINC00239 may function as an oncogenic lncRNA in ESCC through the LINC00239/MBP-1/c-Myc axis to activate EMT process.
Data from HDAC3 Is Required for XPC Recruitment and Nucleotide Excision Repair of DNA Damage Induced by UV Irradiation
Authors: Nishimoto Koji , Niida Hiroyuki , Uchida Chiharu , Ohhata Tatsuya , Kitagawa Kyoko , Motegi Akira , Suda Takafumi , Kitagawa Masatoshi
Published: April 2023

Abstract
Recent studies have demonstrated that lysine acetylation of histones is crucial for nucleotide excision repair (NER) by relaxing the chromatin structure, which facilitates the recruitment of repair factors. However, few studies have focused on the contribution of histone deacetylases (HDAC) to NER. Here, we found that histone H3 Lys14 (H3K14) was deacetylated by HDAC3 after UV irradiation. Depletion of HDAC3 caused defects in cyclobutene pyrimidine dimer excision and sensitized cells to UV irradiation. HDAC3-depleted cells had impaired unscheduled DNA synthesis, but not recovery of RNA synthesis, which indicates that HDAC3 was required for global genome NER. Moreover, xeroderma pigmentosum, complementation group C (XPC) accumulation at the local UV-irradiated area was attenuated in HDAC3-depleted cells. In addition to the delay of XPC accumulation at DNA damage sites, XPC ubiquitylation was inhibited in HDAC3-depleted cells. These results suggest that the deacetylation of histone H3K14 by HDAC3 after UV irradiation contributes to XPC recruitment to DNA lesions to promote global genome NER.
Implications:
Involvement of histone deacetylation for XPC accumulation after UV irradiation indicates conversion of chromatin structure is essential for nucleotide excision repair in human cancer cells.
Data from Proliferation and Self-Renewal Are Differentially Sensitive to NRASG12V Oncogene Levels in an Acute Myeloid Leukemia Cell Line
Authors: Kurata Morito , Antony Marie Lue , Noble-Orcutt Klara E. , Rathe Susan K. , Lee Yoonkyu , Furuno Hidehiro , Ishibashi Sachiko , Ikeda Masumi , Yamamoto Kouhei , Kitagawa Masanobu , Largaespada David A. , Sachs Zohar
Published: April 2023

Abstract
NRAS proteins are central regulators of proliferation, survival, and self-renewal in leukemia. Previous work demonstrated that the effects of oncogenic NRAS in mediating proliferation and self-renewal are mutually exclusive within leukemia subpopulations and that levels of oncogenic NRAS vary between highly proliferative and self-renewing leukemia subpopulations. These findings suggest that NRAS activity levels may be important determinants of leukemic behavior. To define how oncogenic NRAS levels affect these functions, we genetically engineered an acute myeloid leukemia (AML) cell line, THP-1, to express variable levels of NRASG12V. We replaced the endogenous NRASG12D gene with a tetracycline-inducible and dose-responsive NRASG12V transgene. Cells lacking NRASG12V oncoprotein were cell-cycle arrested. Intermediate levels of NRASG12V induced maximal proliferation; higher levels led to attenuated proliferation, increased G1 arrest, senescence markers, and maximal self-renewal capacity. Higher levels of the oncoprotein also induced self-renewal and mitochondrial genes. We used mass cytometry (CyTOF) to define the downstream signaling events that mediate these differential effects. Not surprisingly, we found that the levels of such canonical RAS-effectors as pERK and p4EBP1 correlated with NRASG12V levels. β-Catenin, a mediator of self-renewal, also correlated with NRASG12V levels. These signaling intermediates may mediate the differential effects of NRASG12V in leukemia biology. Together, these data reveal that oncogenic NRAS levels are important determinants of leukemic behavior explaining heterogeneity in phenotypes within a clone. This system provides a new model to study RAS oncogene addiction and RAS-induced self-renewal in AML.
Implications:
Different levels of activated NRAS may exert distinct effects on proliferation and self-renewal.
Data from MOB3A Bypasses BRAF and RAS Oncogene-Induced Senescence by Engaging the Hippo Pathway
Authors: Dutchak Kendall , Garnett Sam , Nicoll Mary , de Bruyns Angeline , Dankort David
Published: April 2023

Abstract
Oncogenic activation of the RTK–RAS–RAF–MEK–ERK pathway occurs in approximately 25% of all human cancers, yet activated RAS, BRAF, or MEK expression in primary cells leads to a prolonged and predominantly irreversible cell-cycle arrest termed oncogene-induced senescence (OIS). OIS acts as an intrinsic tumor suppressor mechanism, serving as a barrier to tumor progression. Screening a library of activated kinases and kinase-regulatory proteins we identified MOB3A, a Mps-one binder coactivator (MOB) protein family member, whose constitutive expression permits proliferation and suppresses senescence in response to oncogenic RAS and BRAF signals. MOB3A is one of seven human MOB genes, which are highly conserved from yeast to human and that function to activate the Hippo pathway kinases (MST/LATS) or NDR kinases through direct association. Here we show that within the MOB family of genes MOB3A and C are unique in their ability to allow primary cell proliferation in the face of sustained oncogene signaling. Unlike the canonical MOB1A/B proteins, MOB3A inhibits Hippo/MST/LATS signaling and constitutive MOB3A membrane localization phenocopies OIS bypass seen with elevated YAP expression. Moreover, inhibition of MOB3 family member expression results in decreased proliferation and tumor growth of cancer cell lines. Together these data identify MOB3A's role in bypass of oncogene induced senescence and its role as a Hippo pathway inhibitor.
Implications:
These results suggest that MOB3 targeting to re-engage the Hippo pathway, or direct targeting of YAP/TAZ, may be viable therapeutic strategies potential for RAS-pathway driven tumours.
Data from A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families
Authors: Zhang Guanyi , Wang Zemin , Bavarva Jasmin , Kuhns Katherine J. , Guo Jianhui , Ledet Elisa M. , Qian Chiping , Lin Yuan , Fang Zhide , Zabaleta Jovanny , Valle Luis Del , Hu Jennifer J. , Mandal Diptasri , Liu Wanguo
Published: April 2023

Abstract
African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families.
Implications:
This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer–risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.
Data from Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression
Authors: Guan Wei , Yang Nan , Zuo Xianglin , Wang Xuchun , Cao Pingping , Chu Ying , Qin Zhongyong , Cheng He , Shi Xiao , Ma Tingzheng , Xu Zekuan , Sun Yujie
Published: April 2023

Abstract
Genome-wide association studies (GWAS) have implicated the 1q22 gastric cancer risk locus in disease, but little is known about its underlying oncogenic functions. This study represents a systematic investigation of the biological significance and potential mechanism associated with the gastric cancer risk of SNP rs2075570(C>T) in 1q22. We identified two functional germline variations (rs2049805-C and rs2974931-G) in an active enhancer in a 64.8 kb high-linkage disequilibrium block of rs2075570. The enhancer upregulated ubiquitin associated protein 2 like (UBAP2L) gene expression over a 960 kb distance by chromatin looping. Gastric cancer tissues expressed significantly higher levels of UBAP2L than was observed in the matched noncancerous tissues, and the UBAP2L expression was negatively correlated with patient survival. Downregulation of UBAP2L inhibited the proliferation and invasion of human gastric cancer cells in vitro and in a xenograft mouse model. Notably, the two mutant variations significantly enforced the enhancer activity and UBAP2L expression. In conclusion, this study revealed two causal variations in the 1q22 region using tag-SNP rs2075570 as a genetic marker. These variations may affect the occurrence and progression of gastric cancer by reinforcing the expression of the 1q22-Enh enhancer-regulated UBAP2L target gene.
Implications:
Our study provides an important clue of how noncoding germline variations contribute to gastric cancer, which gives a novel insight into understanding the genetic mechanism of gastric cancer.
Data from DNA Methyltransferase 3B–Mediated Intratumoral Heterogeneity and Therapeutic Targeting in Breast Cancer Recurrence and Metastasis
Authors: So Jae Young , Yang Howard H. , Park Woo Yong , Skrypek Nicolas , Ishii Hiroki , Chen Jennifer M. , Lee Maxwell P. , Yang Li
Published: April 2023

Abstract
The mechanisms of how cancer cells are selected and evolve to establish distant metastatic colonies remain unclear. Tumor heterogeneity and lack of biomarkers are some of the most difficult challenges in cancer biology and treatment. Here using mouse models for triple-negative breast cancer (TNBC) metastasis, we report heterogeneous expression of DNA methyltransferase 3B (DNMT3B) in both mouse and human primary tumors. High levels of DNMT3B were correlated with poor clinical outcomes in multiple human breast cancer datasets. Mechanistically, clonal cells with high DNMT3B (DNMT3BH) showed higher vimentin (VIM) expression and displayed enhanced epithelial-to-mesenchymal transition capacity. Deletion of VIM diminished the metastatic phenotype of DNMT3BH cells. Importantly, in preclinical mouse models in which the primary tumors were surgically removed, perioperative targeting of DNMT3B in combination with chemotherapy markedly suppressed tumor recurrence and metastasis. Our studies identify DNMT3B-mediated transcription regulation as an important mediator of tumor heterogeneity and show that DNMT3B is critical for tumor invasion and metastasis, reinforcing its potential as a target for treating metastatic disease.
Implications:
Our findings of transcriptome changes mediated by DNMT3B provide new mechanistic insight for intratumor heterogeneity and chemoresistance, and therapeutic targeting of DNMT3B in combination with chemotherapy offer additional treatment options for metastatic disease especially for patients with TNBC.
Data from JAZF1: A Metabolic Regulator of Sensitivity to a Polyamine-Targeted Therapy
Authors: Rosario Spencer R. , Jacobi Justine J. , Long Mark D. , Affronti Hayley C. , Rowsam Aryn M. , Smiraglia Dominic J.
Published: April 2023

Abstract
Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. In addition, it has been shown identification of master metabolic transcriptional regulators (MMTR) of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the MMTRs of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine- and methionine-targeted therapies by identifying novel MMTRs. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a MMTR, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a MMTR of this response.
Implications:
We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.
Data from Circ_0001821 Affects Proliferation and the Cell Cycle in Esophageal Squamous Cell Carcinoma by Elevating BTRC-Mediated IKBA Ubiquitination
Authors: Lin Changjin , Wei Yujun , Duan Xinchun , Liu Chunquan , Du Yanlin , Wang Xiaoran , Luo Yi , Cui Yong
Published: April 2023

Abstract
Esophageal squamous cell carcinoma (ESCC) is a fatal human cancer featured with a tendency to metastasis and relapse. Increasing studies have emphasized the critical roles of circular RNAs (circRNA) in ESCC. This study targeted at a novel circRNA and uncovering its function and mechanisms in ESCC. Functional assays were implemented to evaluate proliferation and cell cycle of ESCC cells. Mechanistic analyses were conducted to explore the potential molecular mechanisms in ESCC cells. In vivo assay was also performed. Based on the collected data, circ_0001821 was highly expressed in ESCC cells. Circ_0001821 knockdown retarded ESCC cell proliferation and tumor growth, while promoting G2–M cell cycle arrest. With regard to its mechanism, RUNX3 promoted PVT1 transcription, further upregulating circ_0001821. Moreover, circ_0001821 sponged miR-423–5p to upregulate BTRC, thus promoting IKBA ubiquitination, and circ_0001821 decreased IKBA expression to activate NF-κB signaling pathway. Rescue assays demonstrated that circ_0001821 facilitated ESCC cell proliferation and cell cycle by downregulating IKBA. In summary, RUNX3-induced circ_0001821 switches on NF-κB signaling pathway via diminishing IKBA expression, functionally prompting ESCC cell proliferation and cell cycle.
Implications:
This study uncovered a novel molecular pathway in ESCC progression, which might provide potential biomarkers for ESCC diagnosis.
Data from COMMD3-Mediated Endosomal Trafficking of HER2 Inhibits the Progression of Ovarian Carcinoma
Authors: Wang Shiqing , Liu Yuxin , Li Siyu , Chen Yanan , Liu Yanhua , Yan Jie , Wu Jiayi , Li Jia , Wang Longlong , Xiang Rong , Shi Yi , Qin Xuan , Yang Shuang
Published: April 2023

Abstract
The dysregulated endocytic traffic of oncogenic receptors, such as the EGFR family especially HER2, contributes to the uncontrolled activation of the downstream oncogenic signaling and progression of various carcinomas, including 90% of ovarian carcinoma. However, the key regulators in the intracellular trafficking of HER2 and their impacts for cancer progression remain largely unknown. In this study, through a genome-wide CRISPR/Cas9 screening for key genes affecting the peritoneal disseminated metastasis of ovarian carcinoma, we identified a member of COMMD family, that is, COMMD3, as a key regulator in the endosomal trafficking of HER2. In the patients with high-grade serous ovarian carcinoma (HGSOC), the expression of COMMD3 is dramatically decreased in the peritoneal disseminated ovarian carcinoma cells comparing with that in the primary ovarian carcinoma cells. COMMD3 greatly inhibits the proliferation, migration, and epithelial–mesenchymal transition (EMT) of HGSOC cells, and dramatically suppresses the tumor growth, the formation of malignant ascites, and the peritoneal dissemination of cancer cells in the orthotopic murine model of HGSOC. Further transcriptome analysis reveals that silencing COMMD3 boosts the activation of HER2 downstream signaling. As a component in the Retriever-associated COMMD/CCDC22/CCDC93 complex responsible for the recognition and recycling of membrane receptors, COMMD3 physically interacts with HER2 for directing it to the slow recycling pathway, leading to the attenuated downstream tumor-promoting signaling.
Implications:
Collectively, this study reveals a novel HER2 inactivation mechanism with a high value for the clinic diagnosis of new ovarian carcinoma types and the design of new therapeutic strategy.
Related Article from Is Prostate Cancer Prevention with Selenium All in the Genes?
Authors: Platz Elizabeth A.
Published: April 2023

Related Article from Is Prostate Cancer Prevention with Selenium All in the Genes?
Supplementary Methods from Combined Serum CA19-9 and miR-27a-3p in Peripheral Blood Mononuclear Cells to Diagnose Pancreatic Cancer
Authors: Wang Wan-Sheng , Liu Ling-Xiao , Li Guo-Ping , Chen Yi , Li Chang-Yu , Jin Da-Yong , Wang Xiao-Lin
Published: April 2023

PDF file - 275K, Normalization method used for sequencing
Perspective from Regulation of Prostaglandin Transporters in Colorectal Neoplasia
Authors: Holla Vijaykumar R. , Backlund Michael G. , Yang Peying , Newman Robert A. , DuBois Raymond N.
Published: April 2023

Perspective from Regulation of Prostaglandin Transporters in Colorectal Neoplasia
Supplementary Figure 2 from Effect of Orally Administered Bovine Lactoferrin on the Growth of Adenomatous Colorectal Polyps in a Randomized, Placebo-Controlled Clinical Trial
Authors: Kozu Takahiro , Iinuma Gen , Ohashi Yasuo , Saito Yutaka , Akasu Takayuki , Saito Daizo , Alexander David B. , Iigo Masaaki , Kakizoe Tadao , Tsuda Hiroyuki
Published: April 2023

Supplementary Figure 2 from Effect of Orally Administered Bovine Lactoferrin on the Growth of Adenomatous Colorectal Polyps in a Randomized, Placebo-Controlled Clinical Trial
Related Article from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Authors: Abba Martín C. , Hu Yuhui , Levy Carla C. , Gaddis Sally , Kittrell Frances S. , Hill Jamal , Bissonnette Reid P. , Brown Powel H. , Medina Daniel , Aldaz C. Marcelo
Published: April 2023

Related Article from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Supplementary Materials from A Genome-Wide Association Study Identifies a Locus on Chromosome 14q21 as a Predictor of Leukocyte Telomere Length and as a Marker of Susceptibility for Bladder Cancer
Authors: Gu Jian , Chen Meng , Shete Sanjay , Amos Christopher I. , Kamat Ashish , Ye Yuanqing , Lin Jie , Dinney Colin P. , Wu Xifeng
Published: April 2023

Supplementary Materials from A Genome-Wide Association Study Identifies a Locus on Chromosome 14q21 as a Predictor of Leukocyte Telomere Length and as a Marker of Susceptibility for Bladder Cancer
Related Article from Isolating the Effects of Social Interactions on Cancer Biology
Authors: Trainor Brian C. , Sweeney Colleen , Cardiff Robert
Published: April 2023

Related Article from Isolating the Effects of Social Interactions on Cancer Biology
Supplementary Table 4 from The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: April 2023

XLS file - 39K, Gene ontology for WT and Pax8 tumors
Supplementary Figure 1 from The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: April 2023

PDF file - 287K, IHC and western data
Related Article from Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung
Authors: Szabo Eva
Published: April 2023

Related Article from Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung
Supplementary Figures and Tables from Tumor Suppressor microRNAs, miR-100 and -125b, Are Regulated by 1,25-dihydroxyvitamin D in Primary Prostate Cells and in Patient Tissue
Authors: Giangreco Angeline A. , Vaishnav Avani , Wagner Dennis , Finelli Antonio , Fleshner Neil , Van der Kwast Theodorus , Vieth Reinhold , Nonn Larisa
Published: April 2023

PDF - 1412KB, Supplementary Figure S1. 50 nM 1,25D is not growth inhibitory in PrE cells. Supplementary Figure S2. Mean levels of miR-100 and miR-125b expression by individual qRT-PCR in DU145, PC3, and commercially available PrEC cells treated with 50 nM 1,25D for 24H. Supplementary Figure S3. miR-100 and miR-125b is negatively correlated with targets PLK1 and E2F3 respectively in PrE cells. Supplementary Figure S4. No change in basal levels of miR-100 and miR-125b and their targets in the normal/cancer prostate cell line pair RWPE-1 and -2. Supplementary Figure S5. MiR-125b decreases migration of PrE cells. Migration was measured 0-48H after scratch in PrE cells transfected with pre-miRs (negative, -100, -125b). Supplementary Figure S6 Basal VDR levels of PrE, LNCaP, RWPE-1, and RWPE-2 cells. Supplementary Figure S7. EZH2 expression in benign and PCa patient tissue. Supplementary Figure S8. Let-7a is decreased in PCa and is positively correlated with prostatic 1,25D in patient tissue. Table S1. TaqMan Assay IDs for PCR. Table S2. miRNAs altered by 1,25D in primary prostatic PrE cells. Table S3. 1,25D-regulated miRNAs changes in PrE cells. Table S4. miR-100 and miR-125b alter growth of PrE, LNCaP, and RWPE-2 cells. Table S5. miRNAs are downregulated in PCa. Table S6. Spearman correlation of miRNAs to vitamin D metabolites.
Supplementary Table 1 from Effects of Human Oral Mucosal Tissue, Saliva, and Oral Microflora on Intraoral Metabolism and Bioactivation of Black Raspberry Anthocyanins
Authors: Mallery Susan R. , Budendorf Deric E. , Larsen Matthew P. , Pei Ping , Tong Meng , Holpuch Andrew S. , Larsen Peter E. , Stoner Gary D. , Fields Henry W. , Chan Kenneth K. , Ling Yonghua , Liu Zhongfa
Published: April 2023

PDF file - 83K
Supplementary Table 5 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Authors: Wu Xifeng , Spitz Margaret R. , Lee J. Jack , Lippman Scott M. , Ye Yuanqing , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Lotan Reuben , Hong Waun K.
Published: April 2023

Supplementary Table 5 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Supplementary Tables 1 - 2 from Erb-041, an Estrogen Receptor-β Agonist, Inhibits Skin Photocarcinogenesis in SKH-1 Hairless Mice by Downregulating the WNT Signaling Pathway
Authors: Chaudhary Sandeep C. , Singh Tripti , Talwelkar Sarang S. , Srivastava Ritesh K. , Arumugam Aadithya , Weng Zhiping , Elmets Craig A. , Afaq Farrukh , Kopelovich Levy , Athar Mohammad
Published: April 2023

PDF file - 43K, Supplementary table 1. Description of antibodies used in this study. Supplementary table 2. Description of primers used in this study.
Supplementary Table 3 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Authors: Wu Xifeng , Spitz Margaret R. , Lee J. Jack , Lippman Scott M. , Ye Yuanqing , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Lotan Reuben , Hong Waun K.
Published: April 2023

Supplementary Table 3 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Supplementary Figure 1 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Authors: Wu Xifeng , Spitz Margaret R. , Lee J. Jack , Lippman Scott M. , Ye Yuanqing , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Lotan Reuben , Hong Waun K.
Published: April 2023

Supplementary Figure 1 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Supplementary Figure 2 from Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCMin/+ Mice by Licofelone, a Novel Dual 5-LOX/COX Inhibitor: Potential Implications for Human Colon Cancer Prevention
Authors: Mohammed Altaf , Janakiram Naveena B. , Li Qian , Choi Chang-In , Zhang Yuting , Steele Vernon E. , Rao Chinthalapally V.
Published: April 2023

PDF file - 173KB
Supplementary Materials from Identification of Gene Signatures and Molecular Markers for Human Lung Cancer Prognosis using an In vitro Lung Carcinogenesis System
Authors: Kadara Humam , Lacroix Ludovic , Behrens Carmen , Solis Luisa , Gu Xuemin , Lee J. Jack , Tahara Eiji , Lotan Dafna , Hong Waun Ki , Wistuba Ignacio I. , Lotan Reuben
Published: April 2023

Supplementary Materials from Identification of Gene Signatures and Molecular Markers for Human Lung Cancer Prognosis using an In vitro Lung Carcinogenesis System