bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from AXL Is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer
Authors: Du Wenting , Phinney Natalie Z. , Huang Huocong , Wang Zhaoning , Westcott Jill , Toombs Jason E. , Zhang Yuqing , Beg Muhammad S. , Wilkie Thomas M. , Lorens James B. , Brekken Rolf A.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the United States, has a high metastatic rate, and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, is a driver of metastasis and immune suppression in multiple cancer types. Here we use single-cell RNA-sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of epithelial-to-mesenchymal transition. We demonstrate that AXL deficiency extends survival, reduces primary and metastatic burden, and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, we demonstrate that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA.
Implications:
These studies implicate AXL as a marker of undifferentiated PDA cells and a target for therapy.
Data from The Ubiquitin-Specific Peptidase USP18 Promotes Lipolysis, Fatty Acid Oxidation, and Lung Cancer Growth
Authors: Liu Xi , Lu Yun , Chen Zibo , Liu Xiuxia , Hu Weiguo , Zheng Lin , Chen Yulong , Kurie Jonathan M. , Shi Mi , Mustachio Lisa Maria , Adresson Thorkell , Fox Stephen , Roszik Jason , Kawakami Masanori , Freemantle Sarah J. , Dmitrovsky Ethan
Published: March 2024

Abstract
Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios, and cold sensitivity. USP18 is a regulator of lipid and fatty acid metabolism. Prior work established that USP18 promotes lung tumorigenesis. We sought to learn whether this occurs through altered lipid and fatty acid metabolism. Loss of USP18 repressed adipose triglyceride lipase (ATGL) expression; gain of USP18 expression upregulated ATGL in lung cancer cells. The E1-like ubiquitin activating enzyme promoted ISG15 conjugation of ATGL and destabilization. Immunoprecipitation assays confirmed that ISG15 covalently conjugates to ATGL. Protein expression of thermogenic regulators was examined in brown fat of USP18-null versus wild-type mice. Uncoupling protein 1 (UCP1) was repressed in USP18-null fat. Gain of USP18 expression augmented UCP1 protein via reduced ubiquitination. Gain of UCP1 expression in lung cancer cell lines enhanced cellular proliferation. UCP1 knockdown inhibited proliferation. Beta-hydroxybutyrate colorimetric assays performed after gain of UCP1 expression revealed increased cellular fatty acid beta-oxidation, augmenting fatty acid beta-oxidation in Seahorse assays. Combined USP18, ATGL, and UCP1 profiles were interrogated in The Cancer Genome Atlas. Intriguingly, lung cancers with increased USP18, ATGL, and UCP1 expression had an unfavorable survival. These findings reveal that USP18 is a pharmacologic target that controls fatty acid metabolism.
Implications:
USP18 is an antineoplastic target that affects lung cancer fatty acid metabolism.
Data from G9a Promotes Invasion and Metastasis of Non–Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway
Authors: Sun Ting , Zhang Keqiang , Pangeni Rajendra P. , Wu Jun , Li Wendong , Du Yong , Guo Yuming , Chaurasiya Shyambabu , Arvanitis Leonidas , Raz Dan J.
Published: March 2024

Abstract
Potential roles of euchromatic histone methyltransferase 2 (EHMT2 or G9a) in invasion and metastasis are not well understood in non–small cell lung cancer (NSCLC). Here, we investigated the effect and underlying mechanisms of G9a and therapeutic implications of targeting G9a in the invasion and metastasis of NSCLC. Overexpression of G9a significantly enhanced in vitro proliferation and invasion, while knockdown of G9a drastically suppressed in vivo growth and metastasis of A549 and H1299 NSCLC cells. Knockdown or inhibition of G9a significantly decreased the expression of focal adhesion kinase (FAK) protein and activation of FAK pathway. In addition, defactinib, a potent FAK inhibitor, partially abolished the G9a-enhanced invasion in these NSCLC cells. Furthermore, targeting G9a was found to suppress NF-κB transcriptional activity in NSCLC cells through stabilizing NF-κB inhibitor alpha (IκBα), while an NF-κB inhibitor Parthenilide partially abolished the G9a-enhanced FAK activation, which suggests that G9a-enhanced invasion and activation of FAK is mediated by elevated NF-κB activity. Notably, a strong positive correlation between the IHC staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408).
Implications:
The findings of this study strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.
Data from Distinct Genomic Alterations in Prostate Tumors Derived from African American Men
Authors: Liu Wennuan , Zheng S. Lilly , Na Rong , Wei Lin , Sun Jishan , Gallagher Johnie , Wei Jun , Resurreccion W. Kyle , Ernst Sarah , Sfanos Karen S. , Isaacs William B. , Xu Jianfeng
Published: March 2024

Abstract
We aim to understand, from acquired genetic alterations in tumors, why African American (AA) men are more likely to develop aggressive prostate cancer. By analyzing somatic mutations in 39 genes using deeper next-generation sequencing with an average depth of 2,522 reads for tumor DNA and genome-wide DNA copy-number alterations (CNA) in prostate cancer in a total of 171 AA/black men and comparing with those in 860 European American (EA)/white men, we here present several novel findings. First, >35% of AA men harbor damaging mutations in APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, each with >1% of mutated copies. Second, among genes with >10% of mutated copies in tumor cells, ZMYM3 is the most frequently mutated gene in AA prostate cancer. In a patient's tumor with >96% frameshift mutations of ZMYM3, we find allelic imbalances in 10 chromosomes, including losses of five and gains of another four chromosomes, suggesting its role in maintaining genomic integrity. Third, when compared to prostate cancer in EA/white men, a higher frequency of CNAs of MYC, THADA, NEIL3, LRP1B, BUB1B, MAP3K7, BNIP3L and RB1, and a lower frequency of deletions of RYBP, TP53, and TMPRSS2-ERG are observed in AA/black men. Finally, for the above genes with higher frequency of CNAs in AA than in EA, deletion of MAP3K7, BNIP3L, NEIL3 or RB1, or gain of MYC significantly associates with both higher Gleason grade and advanced pathologic stage in AA/black men. Deletion of THADA associates with advanced pathologic stage only.
Implications:
A higher frequency of damaging mutation in ZMYM3 causing genomic instability along with higher frequency of altered genomic regions including deletions of MAP3K7, BNIP3L, RB1, and NEIL3, and gain of MYC appear to be distinct somatically acquired genetic alterations that may contribute to more aggressive prostate cancer in AA/black men.
Data from NP-ALT, a Liposomal:Peptide Drug, Blocks p27Kip1 Phosphorylation to Induce Oxidative Stress, Necroptosis, and Regression in Therapy-Resistant Breast Cancer Cells
Authors: Jilishitz Irina , Quiñones Jason Luis , Patel Priyank , Chen Grace , Pasetsky Jared , VanInwegen Allison , Schoninger Scott , Jogalekar Manasi P. , Tsiperson Vladislav , Yan Lingyue , Wu Yun , Gottesman Susan R.S. , Somma Jonathan , Blain Stacy W.
Published: March 2024

Abstract
Resistance to cyclin D-CDK4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer cells, as well as CDK4i-resistant cell types, including triple negative breast cancer (TNBC). The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in nontumor tissues. In HR+ breast cancer cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ERα appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant, and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance.
Implications:
This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.
Data from Cytidine Deaminase APOBEC3A Regulates PD-L1 Expression in Cancer Cells in a JNK/c-JUN-Dependent Manner
Authors: Zhao Kailiang , Zhang Qiang , Flanagan Sheryl A. , Lang Xueting , Jiang Long , Parsels Leslie A. , Parsels Joshua D. , Zou Weiping , Lawrence Theodore S. , Buisson Rémi , Green Michael D. , Morgan Meredith A.
Published: March 2024

Abstract
Programmed death-ligand 1 (PD-L1) promotes tumor immune evasion by engaging the PD-1 receptor and inhibiting T-cell activity. While the regulation of PD-L1 expression is not fully understood, its expression is associated with tumor mutational burden and response to immune checkpoint therapy. Here, we report that Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) is an important regulator of PD-L1 expression. Using an APOBEC3A inducible expression system as well as siRNA against endogenous APOBEC3A, we found that APOBEC3A regulates PD-L1 mRNA and protein levels as well as PD-L1 cell surface expression in cancer. Mechanistically, APOBEC3A-induced PD-L1 expression was dependent on APOBEC3A catalytic activity as catalytically dead APOBEC3A mutant (E72A) failed to induce PD-L1 expression. Furthermore, APOBEC3A-induced PD-L1 expression was dependent on replication-associated DNA damage and JNK/c-JUN signaling but not interferon signaling. In addition, we confirmed the relevance of these finding in patient tumors as APOBEC3A expression and mutational signature correlated with PD-L1 expression in multiple patient cancer types. These data provide a novel link between APOBEC3A, its DNA mutagenic activity and PD-L1-mediated antitumoral immunity. This work nominates APOBEC3A as a mechanism of immune evasion and a potential biomarker for the therapeutic efficacy of immune checkpoint blockade.
Implications:
APOBEC3A catalytic activity induces replication-associated DNA damage to promote PD-L1 expression implying that APOBEC3A-driven mutagenesis represents both a mechanism of tumor immune evasion and a therapeutically targetable vulnerability in cancer cells.
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: March 2024

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 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: March 2024

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 Nestin Is Required for Spindle Assembly and Cell-Cycle Progression in Glioblastoma Cells
Authors: Wang Qinglin , Wu Hao , Hu Jian , Fu Haijuan , Qu Yanghui , Yang Yijun , Cai Kathy Q. , Efimov Andrey , Wu Minghua , Yen Tim , Wang Yuan , Yang Zeng-Jie
Published: March 2024

Abstract
Nestin, a class IV intermediate filament protein, is generally considered as a putative marker of neural stem and progenitor cells in the central nervous system. Glioma is a common type of adult brain tumors, and glioblastoma (GBM) represents the most aggressive form of glioma. Here, we report that Nestin expression is significantly upregulated in human GBM, compared with other types of glioma. Nestin knockdown or deletion in U251 cells and tumor cells from GBM patients derived xenografts resulted in G2–M arrest, finally leading to apoptosis in tumor cells. Using proximity-dependent biotin identification method, we identified βII-tubulin as an interacting protein of Nestin in U251 cells. Nestin stabilized βII-tubulin in U251 cells through physical interaction. Knockdown of Nestin or βII-tubulin disrupted spindle morphology in tumor cells. Our studies further revealed that Nestin deficiency in U251 cells and GBM PDX cells repressed tumor growth upon transplantation. Finally, we found that Nestin deficiency sensitized GBM cells to microtubule-destabilizing drugs such as vinblastine and vincristine. Our studies demonstrate the essential functions and underlying mechanisms of Nestin in the growth and drug response of GBM cells.
Implications:
Through interaction with βII-tubulin, Nestin facilitates cell-cycle progression and spindle assembly of tumor cells in glioblastoma.
Data from Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers
Authors: Hu Zhengbo , Viswanathan Ramya , Cheng Hui , Chen Jianghong , Yang Xinping , Huynh Angel , Clavijo Paul , An Yi , Robbins Yvette , Silvin Christopher , Allen Clint , Ormanoglu Pinar , Martin Scott , Cornelius Shaleeka , Saleh Anthony , Chen Zhong , Van Waes Carter , Morgan Ethan L.
Published: March 2024

Abstract
TNFα is a key mediator of immune and radiotherapy-induced cytotoxicity, but many cancers, including head and neck squamous cell carcinomas (HNSCC), display TNF resistance due to activation of the canonical IKK–NF-κB/RELA pro-survival pathway. However, toxicities associated with direct targeting of the canonical pathway point to the need to identify mechanism(s) contributing to TNFα resistance and synthetic lethal targets to overcome such resistance in cancer cells. Here, RNAi screening for modulators of TNFα–NF-κB reporter activity and cell survival unexpectedly implicated the WEE1 and CDC2 G2–M checkpoint kinases. The IKKα/β-RELA and WEE1-CDC2 signaling pathways are activated by TNFα and form a complex in cell lines derived from both human papillomavirus (−) and (+) subtypes of HNSCC. WEE1 inhibitor AZD1775 reduced IKK/RELA phosphorylation and the expression of NF-κB–dependent pro-survival proteins Cyclin D1 and BCL2. Combination of TNFα and AZD1775 enhanced caspase-mediated apoptosis in vitro, and combination treatment with radiotherapy and AZD1775 potentiated inhibition of HNSCC tumor xenograft growth in vivo, which could be significantly attenuated by TNFα depletion. These data offer new insight into the interplay between NF-κB signaling and WEE1-mediated regulation of the G2–M cell-cycle checkpoint in HNSCC.
Implications:
Inhibiting WEE1 and IKK-RELA crosstalk could potentially enhance the effects of therapies mediated by TNFα with less systemic immune suppression and toxicity than observed with direct interruption of IKK-NF-κB/RELA signaling.
Data from Constitutive β-Catenin Overexpression Represses Lncrna MIR100HG Transcription via HDAC6-Mediated Histone Modification in Colorectal Cancer
Authors: Peng Jian , Ma Yiming , Zhao Xinhua , Yang Xu , Wang Hongying
Published: March 2024

Abstract
Wnt/β-catenin signaling plays a critical role in colonic carcinogenesis. However, non-coding RNAs (ncRNA) transcriptionally regulated by β-catenin are largely unknown. Herein, we found that lncRNA MIR100HG (lnc-MIR100HG) negatively correlated with target genes of β-catenin from The Cancer Genome Atlas colorectal carcinoma database, which was verified in 48 paired colorectal carcinoma specimens. In addition, constitutive overexpression of β-catenin decreased primary and mature lnc-MIR100HG levels, whereas blockage of β-catenin activity with siRNA or inhibitors significantly increased their expression. DNA pull-down and chromatin immunoprecipitation revealed the binding of β-catenin/TCF4 to the MIR100HG promoter. Moreover, β-catenin–forced expression reduced the enrichment of H3K27Ac, an active transcription marker, on the promoter, whereas β-catenin inhibition reversed this effect. Furthermore, HDAC6 was recruited to the MIR100HG promoter and downregulated H3K27Ac enrichment in a β-catenin–dependent manner. Besides, HDAC6 was upregulated and negatively correlated with lnc-MIR100HG in colorectal carcinoma specimens. Functional studies showed that lnc-MIR100HG overexpression induced cell-cycle G0–G1 arrest and repressed cell proliferation via p57 upregulation in vitro and in vivo. Taken together, we found that ectopic β-catenin transcriptionally repressed lnc-MIR100HG expression through HDAC6-mediated histone modification in colorectal carcinoma. Lnc-MIR100HG regulates the cell cycle through p57.
Implications:
It provides a novel downstream mechanism highlighting β-catenin action during colon carcinogenesis and may shed light for further therapeutic approaches.
Data from Transcription Factor FOSL1 Enhances Drug Resistance of Breast Cancer through DUSP7-Mediated Dephosphorylation of PEA15
Authors: Li Lin , Wang Nan , Xiong Youyi , Guo Guangcheng , Zhu Mingzhi , Gu Yuanting
Published: March 2024

Abstract
Breast cancer is one of the commonest malignancies in women with first occurrence and fifth mortality in the world. However, drug resistance has always been a major obstacle to cancer treatment. Transcription factors have been reported to have close association with drug resistance of tumors. Recently, by analyzing the data from Gene Expression Omnibus database (GSE76540), we found that transcription factor FOS like 1, AP-1 transcription factor subunit (FOSL1) was significantly upregulated in the transcriptome of doxorubicin-resistant breast cancer cells compared with that in sensitive parental cells. Therefore, we aim to explore the regulatory mechanism of FOSL1 in affecting the drug resistance of breast cancer cells. FOSL1 expression in doxorubicin-resistant breast cancer cells was firstly examined through qRT-PCR, and then its influence on the drug resistance of breast cancer cells was explored through a series of in vitro and in vivo mechanism assays. Results showed that FOSL1 promoted the drug resistance of breast cancer cells to doxorubicin both in intro and in vivo. It positively regulated the transcription of dual specificity phosphatase 7 (DUSP7) in breast cancer doxorubicin-resistant cells and DUSP7 also enhanced the drug resistance of breast cancer cells. Furthermore, FOSL1 promoted the dephosphorylation of proliferation and apoptosis adaptor protein 15 (PEA15) through DUSP7. In conclusion, it was verified that FOSL1 promoted the drug resistance in breast cancer through DUSP7-mediated dephosphorylation of PEA15.
Implications:
These initial findings suggest that the FOSL1/DUSP7/PEA15 pathway may provide a theoretical guidance for breast cancer treatment.
Data from circ_0041732 Promotes Breast Cancer Progression
Authors: Ye Guolin , He Suqun , Pan Ruilin , Zhu Lewei , Zhou Dan , Cai Genxi , Chen Peixian
Published: March 2024

Abstract
Breast cancer is quite a prevalent cancer worldwide, and it is the leading cause of cancer-related deaths among female populations worldwide. Increasingly more efforts have been made in exploration of circular RNA functions in various malignancies. In this study, the primary target was to verify the putative influences of circ_0041732 on breast cancer progression and the corresponding regulatory mechanism. In addition to measurement of RNAs and proteins, functional assays were done to examine the changes in cell proliferation and cell cycle, and the potential association among genes was investigated by mechanism assays. According to experimental results, significant upregulation of circ_0041732 was confirmed in breast cancer tissues and cell lines. E2F4 was proved to transcriptionally modulate circ_0041732. Moreover, circ_0041732 was validated to accelerate breast cancer cell proliferation and impede G2–M arrest and cell apoptosis, and the oncogenic role of circ_0041732 in breast cancer was further verified via in vivo experiments. circ_0041732 could sponge miR-541-3p to enhance expression levels of RelA and GLI4, thus activating NFκB and Hedgehog pathways and affecting breast cancer cell proliferation, cell cycle, and apoptosis. In all, E2F4-mediated circ_0041732 could activate RelA/NFκB and GLI4/Hedgehog signaling pathways via modulation on miR-541-3p/RelA/GLI4 to promote breast cancer progression.
Implications:
E2F4-mediated circ_0041732 upregulation resulted in the activation of NFκB and Hedgehog pathways via sponging miR-541-3p and enhancing expression levels of RelA and GLI4, thus affecting breast cancer cell proliferation, cell cycle, and cell apoptosis.
Data from GATM-Mediated Creatine Biosynthesis Enables Maintenance of FLT3-ITD–Mutant Acute Myeloid Leukemia
Authors: Zhang Yuan , Newsom Kimberly J. , Zhang Mei , Kelley Jeffry S. , Starostik Petr
Published: March 2024

Abstract
FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML), with the most common mutation being internal tandem duplications (ITD). The presence of FLT3-ITD in AML carries a particularly poor prognosis and renders therapeutic resistance. New druggable targets are thus needed in this disease. In this study, we demonstrate the effects of de novo creatine biosynthesis upregulation by FLT3-ITD on AML sustainability. Our data show that FLT3-ITD constitutively activates the STAT5 signaling pathway, which upregulates the expression of glycine amidinotransferase (GATM), the first rate-limiting enzyme of de novo creatine biosynthesis. Pharmacologic FLT3-ITD inhibition reduces intracellular creatinine levels through transcriptional downregulation of genes in the de novo creatine biosynthesis pathway. The same reduction can be achieved by cyclocreatine or genetic GATM knockdown with shRNA and is reflected in significant decrease of cell proliferation and moderate increase of cell apoptosis in FLT3-ITD–mutant cell lines. Those effects are at least partially mediated through the AMPK/mTOR signaling pathway. This study uncovers a previously uncharacterized role of creatine metabolic pathway in the maintenance of FLT3-ITD–mutant AML and suggests that targeting this pathway may serve as a promising therapeutic strategy for FLT3-ITD–positive AML.
Implications:
FLT3-ITD mutation in AML upregulates de novo creatine biosynthesis that we show can be suppressed to diminish the proliferation and survival of blast cells.
Data from MUC1-C Dictates JUN and BAF-Mediated Chromatin Remodeling at Enhancer Signatures in Cancer Stem Cells
Authors: Bhattacharya Atrayee , Fushimi Atsushi , Yamashita Nami , Hagiwara Masayuki , Morimoto Yoshihiro , Rajabi Hasan , Long Mark D. , Abdulla Maha , Ahmad Rehan , Street Kelly , Liu Song , Liu Tao , Kufe Donald
Published: March 2024

Abstract
The oncogenic MUC1-C protein promotes dedifferentiation of castrate-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) cells. Chromatin remodeling is critical for the cancer stem cell (CSC) state; however, there is no definitive evidence that MUC1-C regulates chromatin accessibility and thereby expression of stemness-associated genes. We demonstrate that MUC1-C drives global changes in chromatin architecture in the dedifferentiation of CRPC and TNBC cells. Our results show that MUC1-C induces differentially accessible regions (DAR) across their genomes, which are significantly associated with differentially expressed genes (DEG). Motif and cistrome analysis further demonstrated MUC1-C–induced DARs align with genes regulated by the JUN/AP-1 family of transcription factors. MUC1-C activates the BAF chromatin remodeling complex, which is recruited by JUN in enhancer selection. In studies of the NOTCH1 gene, which is required for CRPC and TNBC cell self-renewal, we demonstrate that MUC1-C is necessary for (i) occupancy of JUN and ARID1A/BAF, (ii) increases in H3K27ac and H3K4me3 signals, and (iii) opening of chromatin accessibility on a proximal enhancer–like signature. Studies of the EGR1 and LY6E stemness–associated genes further demonstrate that MUC1-C–induced JUN/ARID1A complexes regulate chromatin accessibility on proximal and distal enhancer–like signatures. These findings uncover a role for MUC1-C in chromatin remodeling that is mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state.
Implications:
These findings show that MUC1-C, which is necessary for the CRPC and TNBC CSC state, activates a novel pathway involving JUN/AP-1 and ARID1A/BAF that regulates chromatin accessibility of stemness-associated gene enhancers.
Data from TGF-β-Induced FLRT3 Attenuation Is Essential for Cancer-Associated Fibroblast–Mediated Epithelial–Mesenchymal Transition in Colorectal Cancer
Authors: Yang Mengdi , Li Dan , Jiang Zhiyuan , Li Changcan , Ji Suyuan , Sun Jing , Chang Yujie , Ruan Shunyi , Wang Zhiyu , Liang Rui , Dai Xueyu , Li Bin , Zhao Hui
Published: March 2024

Abstract
Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. The effects of CAFs on the progression of colorectal cancer remain controversial. In this study, we found the ectopic overexpression of Fibronectin leucine-rich transmembrane protein 3 (FLRT3) inhibited the process of epithelial–mesenchymal transition (EMT), as well as the proliferation, migration, invasion, and promote apoptosis of colorectal cancer cells, whereas silencing FLRT3 expression resulted in the opposite phenomenon. FLRT3 downregulation was associated with a poor prognosis in colorectal cancer. Also, FLRT3 expression was significantly related to some clinicopathologic factors, including T stage (P = 0.037), N stage (P = 0.042), and E-cadherin (P = 0.002) level. Via univariate and multivariate analyses, M stage (P < 0.0001), FLRT3 (P = 0.044), and E-cadherin (P = 0.003) were associated with overall survival and were independent prognostic factors for it. Mechanistically, CAFs secreted TGF-β, which downregulated FLRT3 expression by activating SMAD4 to promote aggressive phenotypes in colorectal cancer cells. Moreover, FLRT3 repressed tumorigenesis and lung metastasis, which could be reversed by LY2109761, a dual inhibitor of TGF-β receptor type I and II. Treatment with LY2109761 increased IFN-γ expression in CD8+ T cells and reduced the number of regulatory T cells in the tumor microenvironment. Taken together, we revealed the metastasis-suppressive function of FLRT3, which was attenuated during the CAFs-mediated activation of the TGF-β/SMAD4 signaling pathway to promote EMT in colorectal cancer. LY2109761 that significantly inhibited metastasis could be a new treatment option for advanced colorectal cancer.
Implications:
CAFs enhance colorectal cancer aggressiveness by reducing FLRT3 expression through activating TGF-β/SMAD4 signaling pathway. CAF-targeted therapy and/or LY2109761 were promising treatments for colorectal cancer.
Data from Epigenetic Silencing of BMP6 by the SIN3A–HDAC1/2 Repressor Complex Drives Melanoma Metastasis via FAM83G/PAWS1
Authors: Min Dongkook , Byun Jaemin , Lee Eun-Joon , Khan Abdul A. , Liu Christina , Loudig Oliver , Hu Wei , Zhao Yong , Herlyn Meenhard , Tycko Benjamin , Cole Phillip A. , Ryu Byungwoo
Published: March 2024

Abstract
Aberrant epigenetic transcriptional regulation is linked to metastasis, a primary cause of cancer-related death. Dissecting the epigenetic mechanisms controlling metastatic progression may uncover important insights to tumor biology and potential therapeutic targets. Here, we investigated the role of the SIN3A histone deacetylase 1 and 2 (SIN3A–HDAC1/2) complex in cancer metastasis. Using a mouse model of melanoma metastasis, we found that the SIN3A–HDAC1/2 transcription repressor complex silences BMP6 expression, causing increased metastatic dissemination and tumor growth via suppression of BMP6-activated SMAD5 signaling. We further discovered that FAM83G/PAWS1, a downstream effector of BMP6–SMAD5 signaling, contributes critically to metastatic progression by promoting actin-dependent cytoskeletal dynamics and cell migration. Pharmacologic inhibition of the SIN3A–HDAC1/2 complex reduced the numbers of melanoma cells in the circulation and inhibited metastatic tumor growth by inducing disseminated cell dormancy, highlighting the SIN3A–HDAC1/2 repressor complex as a potential therapeutic target for blocking cancer metastasis.
Implications:
This study identifies the novel molecular links in the metastatic progression to target cytoskeletal dynamics in melanoma and identifies the SIN3A–HDAC1/2 complex and FAM83G/PAWS1 as potential targets for melanoma adjuvant therapy.
Data from Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition
Authors: Rahman Masum , Olson Ian , Mansour Moustafa , Carlstrom Lucas P. , Sutiwisesak Rujapope , Saber Rehan , Rajani Karishma , Warrington Arthur E. , Howard Adam , Schroeder Mark , Chen Sisi , Decker Paul A. , Sananikone Eliot F. , Zhu Yi , Tchkonia Tamar , Parney Ian F. , Burma Sandeep , Brown Desmond , Rodriguez Moses , Sarkaria Jann N. , Kirkland James L. , Burns Terry C.
Published: March 2024

Abstract
Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called “senolytic” drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect.
Implications:
These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced BCL-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.
Data from EXOC4 Promotes Diffuse-Type Gastric Cancer Metastasis via Activating FAK Signal
Authors: Li Haojie , Fu Xuhong , Zhao Junjie , Li Chen , Li Lingmeng , Xia Peiyan , Guo Jianping , Wei Wenyi , Zeng Rong , Wu Jiarui , Sun Yihong , Huang Liyu , Wang Xuefei
Published: March 2024

Abstract
In comparison with intestinal-type gastric cancer, diffuse-type gastric cancer (DGC) is more likely to recur, metastasize, and exhibit worse clinical outcomes; however, the underlying mechanism of DGC recurrence remains elusive. By employing an LC/MS-MS proteomic approach, we identified that exocyst complex component 4 (EXOC4) was significantly upregulated in DGC with recurrence, compared to those with nonrecurrence. High expression of EXOC4 was correlated with tumor metastasis and poor prognosis in patients with DGC. Moreover, EXOC4 promoted cell migration and invasion as well as the tumor metastasis of DGC cells. Mechanistically, EXOC4 regulated the phosphorylation of focal adhesion kinase (FAK) at Y397 sites by stimulating the secretion of integrin α5/β1/EGF and enhancing the interaction of FAK and integrin or EGFR. The FAK inhibitor VS-4718 reversed the metastasis mediated by EXOC4 overexpression and suppressed the tumor growth of patient-derived xenografts derived from DGC with high EXOC4 expression. The EXOC4–FAK axis could be a potential therapeutic target for patients with DGC with high expression of EXOC4.
Implications:
The EXOC4–FAK axis promoted DGC metastasis and could be a potential therapeutic target for patients with DGC.
Data from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
Authors: Gao Xueliang , Wang Yubao , Ribeiro Caroline F. , Manokaran Cherubin , Chang Hyeyoun , Von Thanh , Rodrigues Silvia , Cizmecioglu Onur , Jia Shidong , Korpal Manav , Korn Joshua M. , Wang Zhigang , Schmit Fabienne , Jiang Lan , Pagliarini Raymond , Yang Yi , Sethi Isha , Signoretti Sabina , Yuan Guo-Cheng , Loda Massimo , Zhao Jean J. , Roberts Thomas M.
Published: March 2024

Abstract
A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110β inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110β/RAC/PAK1 and β-catenin pathways in CRPC, we found that combining p110β with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110β activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC.
Implications:
This work establishes p110β as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.
Data from Protein Phosphatase 2A–Dependent Mitotic hnRNPA1 Dephosphorylation and TERRA Formation Facilitate Telomere Capping
Authors: Sui Jiang-Dong , Tang Zheng , Chen Benjamin P.C. , Huang Ping , Yang Meng-Qi , Wang Nuo-Han , Yang Hao-Nan , Tu Hong-Lei , Jiang Qing-Ming , Zhang Jing , Wang Ying , Wu Yong-Zhong
Published: March 2024

Abstract
The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2–M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ataxia telangiectasia and Rad3-related (ATR)-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance.
Implications:
This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.
Data from T-cell Dysfunction upon Expression of MYC with Altered Phosphorylation at Threonine 58 and Serine 62
Authors: Daniel Colin J. , Pelz Carl , Wang Xiaoyan , Munks Michael W. , Ko Aaron , Murugan Dhaarini , Byers Sarah A. , Juarez Eleonora , Taylor Karyn L. , Fan Guang , Coussens Lisa M. , Link Jason M. , Sears Rosalie C.
Published: March 2024

Abstract
As a transcription factor that promotes cell growth, proliferation, and apoptosis, c-MYC (MYC) expression in the cell is tightly controlled. Disruption of oncogenic signaling pathways in human cancers can increase MYC protein stability, due to altered phosphorylation ratios at two highly conserved sites, Threonine 58 (T58) and Serine 62 (S62). The T58 to Alanine mutant (T58A) of MYC mimics the stabilized, S62 phosphorylated, and highly oncogenic form of MYC. The S62A mutant is also stabilized, lacks phosphorylation at both Serine 62 and Threonine 58, and has been shown to be nontransforming in vitro. However, several regulatory proteins are reported to associate with MYC lacking phosphorylation at S62 and T58, and the role this form of MYC plays in MYC transcriptional output and in vivo oncogenic function is understudied. We generated conditional c-Myc knock-in mice in which the expression of wild-type MYC (MYCWT), the T58A mutant (MYCT58A), or the S62A mutant (MYCS62A) with or without expression of endogenous Myc is controlled by the T-cell–specific Lck-Cre recombinase. MYCT58A expressing mice developed clonal T-cell lymphomas with 100% penetrance and conditional knock-out of endogenous Myc accelerated this lymphomagenesis. In contrast, MYCS62A mice developed clonal T-cell lymphomas at a much lower penetrance, and the loss of endogenous MYC reduced the penetrance while increasing the appearance of a non-transgene driven B-cell lymphoma with splenomegaly. Together, our study highlights the importance of regulated phosphorylation of MYC at T58 and S62 for T-cell transformation.
Implications:
Dysregulation of phosphorylation at conserved T58 and S62 residues of MYC differentially affects T-cell development and lymphomagenesis.
Data from Cruciferous Vegetable Feeding Alters UGT1A1 Activity: Diet- and Genotype-Dependent Changes in Serum Bilirubin in a Controlled Feeding Trial
Authors: Navarro Sandi L. , Peterson Sabrina , Chen Chu , Makar Karen W. , Schwarz Yvonne , King Irena B. , Li Shuying S. , Li Lin , Kestin Mark , Lampe Johanna W.
Published: March 2024

Abstract
Chemoprevention by isothiocyanates from cruciferous vegetables occurs partly through up-regulation of phase II conjugating enzymes, such as UDP-glucuronosyltransferases (UGT). UGT1A1 glucuronidates bilirubin, estrogens, and several dietary carcinogens. The UGT1A1*28 polymorphism reduces transcription compared with the wild-type, resulting in decreased enzyme activity. Isothiocyanates are metabolized by glutathione S-transferases (GST); variants may alter isothiocyanate clearance such that response to crucifers may vary by genotype. We evaluated, in a randomized, controlled, crossover feeding trial in humans (n = 70), three test diets (single- and double-“dose” cruciferous and cruciferous plus apiaceous) compared with a fruit and vegetable–free basal diet. We measured serum bilirubin concentrations on days 0, 7, 11, and 14 of each 2-week feeding period to monitor UGT1A1 activity and determined effects of UGT1A1*28 and GSTM1/GSTT1-null variants on response. Aggregate bilirubin response to all vegetable-containing diets was statistically significantly lower compared with the basal diet (P < 0.03 for all). Within each UGT1A1 genotype, lower bilirubin concentrations were seen in *1/*1 in both single- and double-dose cruciferous diets compared with basal (P < 0.03 for both); *1/*28 in double-dose cruciferous and cruciferous plus apiaceous compared with basal, and cruciferous plus apiaceous compared with single-dose cruciferous (P < 0.02 for all); and *28/*28 in all vegetable-containing diets compared with basal (P < 0.02 for all). Evaluation of the effects of diet stratified by GST genotype revealed some statistically significant genotypic differences; however, the magnitude was similar and not statistically significant between genotypes. These results may have implications for altering carcinogen metabolism through dietary intervention, particularly among UGT1A1*28/*28 individuals.
Data from Aerosolized 3-Bromopyruvate Inhibits Lung Tumorigenesis without Causing Liver Toxicity
Authors: Zhang Qi , Pan Jing , North Paula E. , Yang Shoua , Lubet Ronald A. , Wang Yian , You Ming
Published: March 2024

Abstract
3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer. Cancer Prev Res; 5(5); 717–25. ©2012 AACR.