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Tumor Discovery RNA-protein complexes deregulated in cancer

USP10, poly-A-binding protein, and Lsm1. YB-1, with The RNA-binding function of G3BP1 is impaired by
its low-complexity sequence domains, activates G3BP1 acetylation at lysine 376 (K376) in its RRM domain. A
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translation, thereby promoting SG assembly. Acetylation of mutation mimicking this acetylation, K376Q, disrupts
YB-1, induced by entinostat, suppresses G3BP1 translation G3BP1 interaction with poly(A)-binding protein 1
and SG formation. YB-1 interaction with G3BP1 also (PABP1) but does not affect interactions with Caprin-1
promotes metastasis in RCC by upregulating secreted or USP10. Substituting G3BP1 with its K376Q mutant or
phosphoprotein 1 (SPP1). an RNA-binding-deficient mutant (F380L/F382L) blocks
SG formation. During SG resolution, K376-acetylated
SGs play a critical role in enhancing tumor growth, 178
invasiveness, migration, apoptosis inhibition, immune G3BP1 is observed outside SGs. MAGE-B2 (melanoma-
associated antigen B2) suppresses SG initiation by reducing
evasion, and metabolic reprogramming. SGs also G3BP levels below the concentration critical for phase
contribute to the development of resistance against separation. G3BP2 also induces changes in condensate
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chemotherapy, immunotherapy, and radiotherapy across and mRNA expression under endoplasmic reticulum (ER)
various cancer types. stress. Residues critical for G3BP condensation, such as
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A small molecule, C108, inhibits G3BP2, delays stress V11, is essential for forming the G3BP-Caprin-1 complex
response, suppresses cancer cell metastasis, and promotes and assembling SGs. 169
CD8 T-cell proliferation and infiltration, improving During arsenite administration, oxidative stress or
survival in animal models with breast tumor xenografts. elongation factor eIF2 phosphorylation causes cell to enter
LINC01554 protects G3BP2 against degradation through a translation arrest phase. In this phase, RNAs are stalled
ubiquitination. RNA-seq analysis has revealed that within a ternary complex comprising eukaryotic initiation
hepatoma-derived growth factor (HDGF) is regulated factor 2 (eIF2)/GTP/Met-tRNA. SGs play a critical role
by G3BP2. G3BP2 binds to HDGF mRNA, stabilizing its during this phase by sequestering mRNAs and inhibiting
expression, while C108 inhibits G3BP2 function. 169 their translation until the stress subsides. Depending on
Cancer cells exploit SGs as condensates to sequester the severity and type of stress, SGs may also lead to the
drugs, protecting cellular components during stress. G3BP1, processing or degradation of mRNAs. SGs contain enzymes
a key nucleation protein in SGs, is highly expressed in of the RNA silencing pathway, including Argonaute2,
various cancers and promotes proliferation, migration, trans-acting factors, Hsp90 complexes, and RBPs, which
and invasion. Although the mechanism underlying the participate in the small RNA-mediated repression of RNA
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upregulation of SG formation is not fully understood, G3BP1 targets. Interestingly, viruses exploit SG formation to their
expression is regulated by Y-box binding protein 1 (YB1), a advantage, either by facilitating the translation of their own
nucleocytoplasmic shuttle protein. YB1 binds to the 5′ UTR RNAs or by binding to SG protein scaffolds to inhibit SG
of G3BP1 mRNA, promoting its translation. Notably, YB1 is formation. 14,15
highly expressed in sarcomas and nasopharyngeal cancers. SGs have been implicated in cancer development and
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SG formation also favors cancer cells by inhibiting apoptosis. neurodegenerative diseases. In human HCC tissues, four
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Drug-based inhibition of SG components, such as DDX3, genes—KPNA2, MEX3A, WDR62, and SFN—are highly
has been shown to reduce SG formation. SG formation can expressed. Knocking down any of these genes reduces
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also be triggered by lipid signaling molecules. Independent HCC cell proliferation by disrupting SG formation.
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of SG formation, G3BP1 contributes to cancer progression A small molecule, C108, binds to G3BP2, decreasing
by participating in growth-related signaling pathways and PD-L1 mRNA and protein levels, increasing CD8 T-cell
promoting EMT in tumors. 176 proliferation and infiltration, and improving survival and
G3BPs (G3BP1 and G3BP2) regulate mRNA expression long-term cures in breast tumor-bearing mice.
outside of SGs through interactions with RNA. They are Raloxifene, an estrogen receptor modulator, prevents
implicated in cancer progression, invasion, metastasis, SG dissolution in glioblastoma cells, induces protein
and viral infections by regulating SG dynamics, RNA synthesis failure, and promotes cell death during hypoxia.
stability, and tumorigenesis. Consequently, compounds Thus, SG modulation can be a promising strategy to target
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that target G3BPs, block SG formation, or promote SG the hypoxic niche of GBM tumors.
dissolution hold potential as therapeutic agents. G3BPs Knockdown of G3bp1 and G3bp2 prevents SG
may serve as therapeutic targets for both antiviral and formation in response to eIF2α phosphorylation or
anticancer strategies. 177-179
eIF4A inhibition, although cells remain SG-competent
G3BP1 is a central player in SG dynamics, with under heat or osmotic stress. CAPRIN1 binding to G3BP
its RNA-binding ability essential for SG formation. promotes SG formation, whereas USP10 binding inhibits

Volume 3 Issue 4 (2024) 12 doi: 10.36922/td.4657