Cancer cell adaptability: turning ribonucleoprotein granules into targets
Authors: Margot Lavalée, Nicolas Curdy, Camille Laurent, Jean-Jacques Fournié, Don-Marc Franchini
Journal: Trends in cancer (2021)

Ribonucleoprotein (RNP) complexes such as stress granules (SGs) and processing (P) bodies control mRNA translation and availability in cells.Cancer cells must adjust their translational activity to the hostile conditions faced during their formation, progression, and metastasis.Cancer cells use SGs and P-bodies to adapt to various stresses, especially those encountered within the tumor microenvironment and during chemotherapeutic treatments.High expression of proteins crucial for the dynamics of RNP granules in cancer is associated with poor prognosis.The diversity of RNP granule composition and of the regulatory mechanisms involved in their formation and dissociation offers a panel of potential therapeutic targets to control resistance mechanisms of cancer cells. Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies. Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies. Regulating the expression of the genomic information is crucial to ensure cell identity and functionality. During transformation into cancer cells and throughout tumor progression, cells dynamically modulate the expression of their genomic information to adapt to environmental cues. Control of mRNA translation ensures the spatiotemporal adjustment of protein synthesis, and is often dysregulated in cancer cells to favor their adaptability [1.Lee L.J. et al.Cancer plasticity: the role of mRNA translation.Trends Cancer. 2021; 7: 134-145Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In particular, regulation of translation initiation allows cancer cells to reprogram this activity towards essential mRNAs, such as those encoding oncogenes, to facilitate cell growth, proliferation, and survival [2.Chu J. et al.Translation initiation factors: reprogramming protein synthesis in cancer.Trends Cell Biol. 2016; 26: 918-933Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. 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Four stress-sensor kinases can induce eIF2α phosphorylation, namely the PKR-like endoplasmic reticulum kinase (PERK), general control nonrepressible 2 (GCN2), heme-regulated inhibitor (HRI), and protein kinase R (PKR). The outcome of ISR activation is a global decrease in protein synthesis, while sparing the translation of some specific mRNAs such as that of transcription factor ATF4 [4.Costa-Mattioli M. Walter P. The integrated stress response: from mechanism to disease.Science. 2020; 368eaat5314Crossref PubMed Scopus (42) Google Scholar]. Activation of this pathway, and the resulting selective translation, favor tumor progression following endoplasmic reticulum stress caused for instance by the hypoxic TME [6.Rozpedek W. et al.The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress.Curr. Mol. Med. 2016; 16: 533-544Crossref PubMed Scopus (261) Google Scholar]. 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Cancer. 2020; 1: 533-545Crossref PubMed Google Scholar]. ISR activation and translational arrest also seed the formation of RNP complexes called SGs [11.Kedersha N.L. et al.RNA-binding proteins Tia-1 and Tiar link the phosphorylation of Eif-2α to the assembly of mammalian stress granules.J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (801) Google Scholar, 12.Kedersha N. et al.Stress granules and processing bodies are dynamically linked sites of mRNP remodeling.J. Cell Biol. 2005; 169: 871-884Crossref PubMed Scopus (966) Google Scholar, 13.Protter D.S.W. Parker R. Principles and properties of stress granules.Trends Cell Biol. 2016; 26: 668-679Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar, 14.Riggs C.L. et al.Mammalian stress granules and P bodies at a glance.J. Cell Sci. 2020; 133jcs242487Crossref PubMed Scopus (13) Google Scholar] (Figure 1). However, their formation can also be triggered independently of eIF2α phosphorylation by interference with cap-dependent translation, either through the mechanistic target of rapamycin (mTOR)/eIF4E-binding protein 1 (4E-BP1) pathway or by dysfunctional eIF4A, highlighting the intricate connection between translation and SGs for mRNA regulation [15.Ivanov P. et al.Stress granules and processing bodies in translational control.Cold Spring Harb. Perspect. Biol. 2019; 11a032813Crossref PubMed Scopus (99) Google Scholar]. In addition to SGs, RNA fate is also controlled by another type of RNP granule, the P-body [15.Ivanov P. et al.Stress granules and processing bodies in translational control.Cold Spring Harb. Perspect. Biol. 2019; 11a032813Crossref PubMed Scopus (99) Google Scholar,16.Standart N. Weil D. P-bodies: cytosolic droplets for coordinated mRNA storage.Trends Genet. 2018; 34: 612-626Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]. 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We describe here the ability of SGs and P-bodies to provide cancer cells with a functional platform for facing the diverse adverse conditions that cells encounter, and we highlight the different approaches that could be undertaken in a therapeutic perspective. RNP granules are assemblies of proteins and mRNA that progressively aggregate into large macromolecular complexes. RNP assembly is highly dynamic in response to cellular changes and relies on mRNA and nucleating proteins. Stress-dependent signaling provides an influx of untranslated mRNAs that serve as a platform for RNP assembly [31.Kedersha N. et al.Evidence that ternary complex (eIF2–GTP–tRNAiMet)-deficient preinitiation complexes are core constituents of mammalian stress granules.Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (390) Google Scholar,32.Teixeira D. Processing bodies require RNA for assembly and contain nontranslating mRNAs.RNA. 2005; 11: 371-382Crossref PubMed Scopus (483) Google Scholar], where specific RBPs are crucial for the formation of the granules. For SGs, Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are the major nucleating determinants [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19.Yang P. et al.G3BP1 is a tunable switch that triggers phase separation to assemble stress granules.Cell. 2020; 181: 325-345Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 20.Guillén-Boixet J. et al.RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation.Cell. 2020; 181: 346-361Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar,33.Tourrière H. et al.The RasGAP-associated endoribonuclease G3BP assembles stress granules.J. Cell Biol. 2003; 160: 823-831Crossref PubMed Scopus (563) Google Scholar], whereas T cell-restricted intracellular antigen-1 (TIA1) or TIA1-related protein (TIAR), ubiquitin-associated protein 2-like (UBAP2L), and cell cycle-associated protein 1 (CAPRIN1) have important functions in further RNP aggregation [14.Riggs C.L. et al.Mammalian stress granules and P bodies at a glance.J. Cell Sci. 2020; 133jcs242487Crossref PubMed Scopus (13) Google Scholar,25.Hofmann S. et al.Molecular mechanisms of stress granule assembly and disassembly.Biochim. Biophys. Acta Mol. Cell Res. 2021; 1868118876Crossref PubMed Scopus (8) Google Scholar]. For P-bodies, DEAD-Box ATP-dependent RNA helicase 6 (DDX6), protein LSM14 homolog A (LSM14A), and eukaryotic translation initiation factor 4E transporter (4E-T) are essential nucleating proteins, while mRNA-decapping enzymes 1A and 2 (DCP1A and DCP2, respectively) and enhancer of mRNA-decapping proteins 3 and 4 (EDC3 and EDC4, respectively) strengthen the interaction within the protein network and allow stress-dependent P-body aggregation [14.Riggs C.L. et al.Mammalian stress granules and P bodies at a glance.J. Cell Sci. 2020; 133jcs242487Crossref PubMed Scopus (13) Google Scholar,16.Standart N. Weil D. P-bodies: cytosolic droplets for coordinated mRNA storage.Trends Genet. 2018; 34: 612-626Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar,34.Luo Y. et al.P-Bodies: composition, properties, and functions.Biochemistry. 2018; 57: 2424-2431Crossref PubMed Scopus (127) Google Scholar]. These proteins are usually enriched in intrinsically disordered regions (IDRs) that favor phase separation and RNP granule assembly [35.Protter D.S.W. et al.Intrinsically disordered regions can contribute promiscuous interactions to rnp granule assembly.Cell Rep. 2018; 22: 1401-1412Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. Protein and RNA levels also influence RNP granule formation by modulating protein activity and interactions (RNA–RNA, protein–RNA, and protein–protein) [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19.Yang P. et al.G3BP1 is a tunable switch that triggers phase separation to assemble stress granules.Cell. 2020; 181: 325-345Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 20.Guillén-Boixet J. et al.RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation.Cell. 2020; 181: 346-361Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar,23.Van Treeck B. et al.RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 2734-2739Crossref PubMed Scopus (158) Google Scholar,36.Kim Y. Myong S. RNA remodeling activity of DEAD box proteins tuned by protein concentration, RNA length, and ATP.Mol. Cell. 2016; 63: 865-876Abstract Full Text Full Text PDF PubMed Google Scholar]. In the case of G3BP1, interaction with RNA is essential to induce a conformational change that increases its interacting ability with proteins and RNA, thereby promoting phase separation and SG formation [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,20.Guillén-Boixet J. et al.RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation.Cell. 2020; 181: 346-361Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. In addition, interaction with UBAP2L or CAPRIN1 significantly increases the interacting ability of G3BP1 and favors SG condensation [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. By contrast, ubiquitin-specific peptidase 10 (USP10) negatively regulates SG formation by competing with CAPRIN1 for binding to G3BP1, thereby decreasing the interacting ability of G3BP1 and limiting SG assembly [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,37.Kedersha N. et al.G3BP–Caprin1–USP10 complexes mediate stress granule condensation and associate with 40S subunits.J. Cell Biol. 2016; 212e201508028Crossref Scopus (198) Google Scholar]. This complex network of RNA and protein interactions is further controlled by post-translational modifications (PTMs) that modulate conformational changes and interaction ability, and therefore fine-tune the dynamics of RNP granule assembly and disassembly. Typically, histone deacetylase 6 (HDAC6) deacetylates G3BP1 in its RNA-binding domain, thereby stimulating binding to RNAs, such as c-Myc, and promoting the interaction with other SG components such as poly(A)-binding protein 1 (PABP1) [38.Gal J. et al.The acetylation of lysine-376 of G3BP1 regulates RNA binding and stress granule dynamics.Mol. Cell. Biol. 2019; 39e00052-19Crossref PubMed Scopus (11) Google Scholar]. The interplay between deacetylation and acetylation of G3BP1 favor the assembly and disassembly of SGs, respectively. Similarly, stress induces demethylation of G3BP1 and UBAP2L, which promotes SG assembly [39.Tsai W.-C. et al.Arginine demethylation of G3BP1 promotes stress granule assembly.J. Biol. 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Arginine demethylation of UBAP2L promotes the interaction with and between G3BP1, G3BP2, and PABP1 [40.Huang C. et al.UBAP2L arginine methylation by PRMT1 modulates stress granule assembly.Cell Death Differ. 2020; 27: 227-241Crossref PubMed Scopus (21) Google Scholar]. Likewise, arginine demethylation in the RGG domain of LSM4 stimulates P-body formation [42.Arribas-Layton M. et al.The C-terminal RGG domain of human Lsm4 promotes processing body formation stimulated by arginine dimethylation.Mol. Cell. Biol. 2016; 36: 2226-2235Crossref PubMed Scopus (25) Google Scholar]. RNP granule formation is therefore the summation of intricate interactions between proteins and RNA that can modulate the interacting ability of crucial proteins to stimulate their accretion. Variation of protein and RNA stoichiometry within these complexes can dramatically impact on their formation. Modulation of G3BP1 expression level influences SG assembly, and its overexpression can trigger SG formation even in absence of exogenous stress [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,33.Tourrière H. et al.The RasGAP-associated endoribonuclease G3BP assembles stress granules.J. Cell Biol. 2003; 160: 823-831Crossref PubMed Scopus (563) Google Scholar]. Similar observations were obtained when P-body markers, such as DCP1A, are overexpressed [43.Kedersha N. Anderson P. Mammalian stress granules and processing bodies.Methods Enzymol. 2007; 431: 61-81Crossref PubMed Scopus (450) Google Scholar]. Moreover, deletion of G3BP1 can be somehow compensated by overexpression of other important factors such as UBAP2L [18.Sanders D.W. et al.Competing protein–RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Cancer cells are characterized by an accumulation of somatic and epigenetic mutations and transcriptomic alterations that are associated with remodeling of the proteome and the establishment of the post-transcriptional regulation adapted to these changes. It is therefore conceivable that, during cellular transformation and throughout cancer progression, the alteration in transcriptional and translational activities results in an increased level of RNA and proteins, including nucleating proteins, and consequently promotes the formation of RNP granules. These intrinsic alterations provide cancer cells with adaptive mechanisms to facilitate survival and proliferation on the one hand, and a platform to rapidly respond to environmental stress on the other (Figure 2). Tumor formation and progression encompass sequential cellular events that all involve RNP granules [30.Anderson P. et al.Stress granules, P-bodies and cancer.Biochim. Biophys. Acta Gene Regul. Mech. 2015; 1849: 861-870Crossref Scopus (191) Google Scholar] (Figure 2). Remarkably, elevated expression of SG markers has been reported in various types of human cancers and predicts a poor prognosis [44.Aulas A. et al.Revisiting the concept of stress in the prognosis of solid tumors: a role for stress granules proteins?.Cancers. 2020; 12: 2470Crossref Scopus (1) Google Scholar]. G3BP1 is implicated in multiple cellular programs controlling cell proliferation, apoptosis, motility, and invasion. Silencing of G3BP1 in colon cancer cells decreases their proliferative ability and enhances their apoptosis [45.Li Y. et al.Overexpression of G3BP1 facilitates the progression of colon cancer by activating β-catenin signaling.Mol. Med. Rep. 2020; 22: 4403-4411PubMed Google Scholar]. In gastric cancer, G3BP1 depletion inhibits tumor growth and metastasis, and cells with a G3BP1 mutation that impairs SG formation are unable to perform cell proliferation, migration, and invasion [46.Min L. et al.Overexpression of Ras-GTPase-activating protein SH3 domain-binding protein 1 correlates with poor prognosis in gastric cancer patients.Histopathology. 2015; 67: 677-688Crossref PubMed Scopus (31) Google Scholar]. Similar results were obtained in gastric, esophageal, and renal cell carcinoma (RCC) cancer cells, where G3BP1 depletion decreases proliferation rates, migration capacity, and invasiveness [47.Xiong R. et al.G3BP1 activates the TGF-β/Smad signaling pathway to promote gastric cancer.OncoTargets Ther. 2019; 12: 7149-7156Crossref PubMed Scopus (7) Google Scholar, 48.Zhang L. et al.Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/β-catenin and PI3K/AKT signaling pathways.J. Cell. Physiol. 2019; 234: 20469-20484Crossref PubMed Scopus (19) Google Scholar, 49.Wang Y. et al.G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas.Cell Death Dis. 2018; 9: 501Crossref PubMed Scopus (0) Google Scholar]. In an in vivo RCC mouse xenograft model, silencing of G3BP1 impairs both tumor growth and metastasis [49.Wang Y. et al.G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas.Cell Death Dis. 2018; 9: 501Crossref PubMed Scopus (0) Google Scholar]. Along these lines, overexpression of G3BP1 exhibits the opposite effects and promotes proliferation, cell migration, and invasion [48.Zhang L. et al.Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/β-catenin and PI3K/AKT signaling pathways.J. Cell. Physiol. 2019; 234: 20469-20484Crossref PubMed Scopus (19) Google Scholar,50.Dou N. et al.G3BP1 contributes to tumor metastasis via upregulation of Slug expression in hepatocellular carcinoma.Am. J. Cancer Res. 2016; 6: 2641-2650PubMed Google Scholar]. G3BP1 is known to participate in the regulation of multiple growth-related signaling pathways involved in carcinogenesis. In non-small-cell lung cancer (NSCLC) and esophageal cancer, G3BP1 activates the PI3K/AKT/mTOR signaling pathway which promotes cell survival [48.Zhang L. et al.Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/β-catenin and PI3K/AKT signaling pathways.J. Cell. Physiol. 2019; 234: 20469-20484Crossref PubMed Scopus (19) Google Scholar,51.Zheng H. et al.Elevated expression of G3BP1 associates with YB1 and p-AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection.Cancer Med. 2019; 8: 6894-6903Crossref PubMed Scopus (11) Google Scholar], whereas G3BP1 promotes gastric cancer through activation of the transforming growth factor (TGF)-β/Smad signaling pathway [47.Xiong R. et al.G3BP1 activates the TGF-β/Smad signaling pathway to promote gastric cancer.OncoTargets Ther. 2019; 12: 7149-7156Crossref PubMed Scopus (7) Google Scholar]. G3BP1 also positively regulates the Wnt/β-catenin signaling axis that drives tumorigenesis and metastasis in colon and esophageal cancer cells [45.Li Y. et al.Overexpression of G3BP1 facilitates the progression of colon cancer by activating β-catenin signaling.Mol. Med. Rep. 2020; 22: 4403-4411PubMed Google Scholar,48.Zhang L. et al.Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/β-catenin and PI3K/AKT signaling pathways.J. Cell. Physiol. 2019; 234: 20469-20484Crossref PubMed Scopus (19) Google Scholar], and stimulates tumor progression and metastasis through the interleukin (IL)-6/G3BP1/STAT3 pathway in RCC cells [49.Wang Y. et al.G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas.Cell Death Dis. 2018; 9: 501Crossref PubMed Scopus (0) Google Scholar]. YB-1, a factor associated with RNP granule biology, activates G3BP1 translation, thereby stimulating SG assembly [52.Somasekharan S.P. et al.YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1.J. Cell Biol. 2015; 208: 913-929Crossref PubMed Scopus (120) Google Scholar]. In human sarcomas, high expression of YB-1 correlates with elevated expression of G3BP1, and this pattern is associated with poor survival [52.Somasekharan S.P. et al.YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1.J. Cell Biol. 2015; 208: 913-929Crossref PubMed Scopus (120) Google Scholar]. Likewise, in NSCLC, G3BP1 and YB-1 expression levels are positively associated with clinical stage and, in RCC, YB-1 expression levels correlate with tumor node metastasis (TNM) stage and metastasis [53.Wang Y. et al.The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1–SPP1–NF-κB signaling axis.J. Exp. Clin. Cancer Res. 2019; 38: 386Crossref PubMed Scopus (7) Google Scholar]. YB-1 interaction with G3BP1 promotes metastasis in RCC by upregulating secreted phosphoprotein 1 (SPP1), a gene regulator of the NF-κB signaling pathway that promotes cancer progression. Silencing YB-1 impairs the migration and invasion of RCC cells, identifying YB-1 as a potent metastatic driver [53.Wang Y. et al.The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1–SPP1–NF-κB signaling axis.J. Exp. Clin. Cancer Res. 2019; 38: 386Crossref PubMed Scopus (7) Google Scholar]. YB-1 also protects against oxidative stress through the translational regulation of NRF2, an antioxidant transcription factor [54.El-Naggar A.M. et al.Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis.EMBO Rep. 2019; 20e48375Crossref PubMed Scopus (12) Google Scholar]. Preventing YB-1 acetylation with the histone deacetylase inhibitor entinostat limits NRF2 translation and provokes the accumulation of reactive oxygen species (ROS), which enhances oxidative stress and apoptosis, and reduces the metastatic abilities of sarcoma cells. Furthermore, entinostat-induced YB-1 acetylation suppresses G3BP1 translation and SG formati