USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC

Abstract

GTPase-activating protein-binding protein 2 (G3BP2) is a key stress granule-associated RNA-binding protein responsible for the formation of stress granules (SGs). Hyperactivation of G3BP2 is associated with various pathological conditions, especially cancers. Emerging evidence indicates that post-translational modifications (PTMs) play critical roles in gene transcription, integrate metabolism and immune surveillance. However, how PTMs directly regulate G3BP2 activity is lacking. Here, our analyses identify a novel mechanism that PRMT5-mediated G3BP2-R468me2 enhances the binding to deubiquitinase USP7, which ensures the deubiquitination and stabilization of G3BP2. Mechanistically, USP7- and PRMT5-dependent G3BP2 stabilization consequently guarantee robust ACLY activation, which thereby stimulating de novo lipogenesis and tumorigenesis. More importantly, USP7-induced G3BP2 deubiquitination is attenuated by PRMT5 depletion or inhibition. PRMT5-activity dependent methylation of G3BP2 is required for its deubiquitination and stabilization by USP7. Consistently, G3BP2, PRMT5 and G3BP2 R468me2 protein levels were found positively correlated in clinical patients and associated with poor prognosis. Altogether, these data suggest that PRMT5-USP7-G3BP2 regulatory axis serves as a lipid metabolism reprogramming mechanism in tumorigenesis, and unveil a promising therapeutic target in the metabolic treatment of head and neck squamous carcinoma.

SP1‐activated USP27X‐AS1 promotes hepatocellular carcinoma progression via USP7‐mediated AKT stabilisation

“…USP7 regulates the function and turnover of a wide range of substrates, including P53, ERK1/2, PD-L1, PRMT5, ANXA1, STAT3 and ECT2, which are crucial components of numerous oncogenic signalling pathways. [46][47][48][49][50][51][52] For example, USP7 is a crucial deubiquitinase needed to stabilise oncogenic versions of DDX3X. By stabilising DDX3X, USP7 increases Wnt/beta-catenin signalling, which has previously been demonstrated to be strongly correlated with colorectal cancer cell invasiveness.…”

“…Deubiquitylases have been implicated with a number of cancers, including HCC, according to recent research. USP7 regulates the function and turnover of a wide range of substrates, including P53, ERK1/2, PD‐L1, PRMT5, ANXA1, STAT3 and ECT2, which are crucial components of numerous oncogenic signalling pathways 46–52 . For example, USP7 is a crucial deubiquitinase needed to stabilise oncogenic versions of DDX3X.…”

ZNF692 promotes the migration and response to immunotherapy of clear cell renal cell carcinoma cells by targeting metabolic pathway

“…G3BP2 was first identified as an androgen-responsive gene, core components that contributes to stress granules (SGs) assembly and RNA metabolism [ 38 ]. Increased G3BP2 promoted the growth of cancer cells and high expression level of G3BP2 was associated with poor prognostic in Head and Neck squamous cell carcinoma, prostate cancer, breast, and lung cancer [ 39 – 42 ]. However, we found that the high expression level G3BP2 was associated with better prognostic in ccRCC.…”

Stress granules in cancer: Adaptive dynamics and therapeutic implications

“… 179 In prostate cancer, research has revealed that G3BP1 interacts with USP7 and PRMT5, contributing to the stabilization of G3BP2 and influencing its ubiquitination status. 180 This in turn affects the functionality of deacetylase SIRT1, ultimately impacting the activity of downstream transcription factors like NF-κB and β-catenin, culminating in an increase in de novo lipid synthesis, thus enhancing the malignancy and drug resistance of the tumor.…”