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Tumor Discovery RNA-protein complexes deregulated in cancer

it. G3BP, through its RGG motif, interacts with 40S P bodies are enriched in mRNAs with m6A
ribosomal subunits, and this motif is essential for G3BP- modifications, attracting the m6A reader YTHDF2, which
mediated SG assembly. G3BP facilitates SG condensation colocalizes with P body markers DCP1A, DDX6, and
through S149 phosphorylation and its interactions with EDC4. DCP1A is post-translationally modified through
CAPRIN1 or USP10. CAPRIN1 is a phase-separating ubiquitination by the E3 ubiquitin ligase TRAF6 and
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protein with significant roles in dendritic spines and phosphorylation. These PTMs favor interactions with P
SG formation, often in association with ncRNAs. body factors such as DCP2, EDC4, and XRN1, enhancing
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SG-associated CAPRIN1 is involved in the progression P body formation. Notably, phosphorylation promotes
of nasopharyngeal carcinoma. In ovarian cancer, mRNA storage, whereas ubiquitination drives mRNA
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the upregulation of SNHG8 RNA enhances its binding decay.
with CAPRIN1, positively regulating its expression and Knockdown of DDX6 in a mouse model of late-stage
promoting the stability of catenin beta 1 (CTNNB1) BC prevents P body formation, inhibits EMT, and reduces
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and Axin. These interactions activate Wnt/β-catenin metastatic nodule size and number. Snail zinc finger
signaling, thereby facilitating cell migration and EMT and transcription factors, which are key regulators of EMT,
maintaining the stemness of ovarian cancer cells. Given are recruited to P bodies by the RNA-binding protein
their pivotal role in cellular stress responses, SGs are muscleblind-like 1 (MBNL1), suppressing metastasis
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promising therapeutic targets for cancer treatment. For formation.
example, small peptides derived from the G3BP1 sequence
have shown encouraging results in cancer therapy. 185 Y-box binding protein 1 (YB-1) activates SNAIL
transcription, promoting EMT and cell invasiveness in
CAPRIN1 is an RNA-binding protein that confers BC. This mechanism is also significant in pancreatic
specificity to enzymes depositing the (m6A) mark cancer and in resistance to gemcitabine. YB-1 additionally
on RNAs, particularly near stop codons. An et al. protects against oxidative stress by regulating NRF2, a
demonstrated that TRA2A and CAPRIN1 promote the transcription factor with antioxidant functions. Several
methylation of m6A sites colocalized with their RNA- inhibitors of YB-1 have been identified, including PI3K/
binding targets. CAPRIN1 interacts with METTL3 and mTOR inhibitors, which suppress YB-1 activity. 184
METTL14, forming the m6A methyltransferase METTL3/
METTL14 complex, which associates with Wilms’ tumor 3.6. Regulation of ncRNAs at the epitranscriptome
1-associated protein (WTAP). 186 level

3.5. P bodies RNA modifications, particularly m6A and m5C, are critical
regulators of RNA structure, stability, and function.
27
P bodies are dynamic structures similar to SGs and are The deposition of m6A induces structural changes in
organized during stress-induced translational arrest. They ncRNAs, altering ncRNA-protein interactions, regulating
serve as sites for mRNA silencing and decay. Specific RBPs transcription, influencing subcellular localization, and
are essential for P body formation, including DEAD- stabilizing ncRNAs. Other RNA modifications include
box RNA helicase 6 (DDX6), LSM14A, and eukaryotic m7G and acetylation marks, such as m1A in MALAT1 and
translation initiation factor 4E transporter (EiF4E), which Ac4C on cytosine. 27,187,188 NAT10 is the enzyme responsible
participate in the nucleation process. Other P body- for the deposition of N4-acetylcytidine (Ac4C), a
associated proteins include SAMD4A, AJUBA, YB-1, and modification implicated in cancer. NAT10 serves as a
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Wilms’ tumor-1 interacting protein (WTIP). Enzymes metastasis suppressor in CRC, acetylating RNA CTC-
such as DCP1A and DCP2 and enhancers of mRNA 490G23.2, which binds to polypyrimidine tract-binding
decapping proteins (EDC3 and EDC4) reinforce the protein 1 (PTBP1) and increases alternative splicing of
protein interaction network and are required for stress- CD44 in esophageal squamous cell carcinoma. However,
induced P body formation. NAT10 may also act as a metastasis promoter and EMT
P bodies are closely linked to tumor progression. In inducer by stabilizing COL5A1 mRNA through direct
CRC, DCP1A is highly expressed, and this upregulation binding. 190
correlates with advanced tumor-node-metastasis stage, The N6-adenosine–methyltransferase complex catalytic
worse prognosis, increased lymph node metastasis, tumor subunit (METTL3) is an S-adenosylmethionine (SAM)-
invasiveness, and lower survival rates. In mammary dependent enzyme. The methyltransferase complex,
epithelial cells, treatment with TGF-β promotes P body formed by METTL3 and METTL14 and associated with
formation and EMT. Activation of autophagy can clear P WTAP, methylates adenines, producing m6A-modified
bodies, thereby blocking EMT. RNAs. Interestingly, METTL14 acts as a chromatin

Volume 3 Issue 4 (2024) 13 doi: 10.36922/td.4657