N⁶‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) ranks fourth among the malignancies leading to cancer‐related deaths all around the world. It is increasingly evident that long non‐coding RNAs (lncRNAs) are a key mode of hepatocarcinogenesis. As the most prevalent mRNA modification form, N6‐methyladenosine (m6A) regulates gene expression by impacting multiple aspects of mRNA metabolism. However, there are still no reports on genome‐wide screening and functional annotation of m6A‐methylated lncRNAs in HCC. Methods The m6A modification and biologic functions of ARHGAP5‐AS1 in HCC were investigated through a series of biochemical assays. Clinical implications of ARHGAP5‐AS1 were examined in tissues from HCC patients. Results After systematically analysing the m6A‐seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m6A levels. Among these lncRNAs, we found that ARHGAP5‐AS1 is the lncRNA with the highest levels of m6A modification and significantly increased expression in HCC specimens. METTL14 acts as the m6A writer of ARHGAP5‐AS1 and IGF2BP2 stabilises the lncRNA as its m6A reader. ARHGAP5‐AS1 remarkably promotes malignant behaviours of HCC cells ex vivo and in vivo. We identified oncoprotein CSDE1 working as the interacting protein of the lncRNA and TRIM28 as the E3 ligase of CSDE1 in HCC. Interestingly, ARHGAP5‐AS1 could attenuate interactions between CSDE1 and TRIM28, which prevents the degradation of CSDE1 via the ubiquitin‐proteasome pathway. Elevated levels of CSDE1 coordinate oncogenic RNA regulons, promote translation of VIM and RAC1 and activate the ERK pathway, which contributes to HCC prognosis. Conclusions Our study reveals a new paradigm in m6A‐modified lncRNAs controlling CSDE1‐mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC.

Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

“…IGF2BP2 stabilizes MSX1 and JARID2 transcripts in an m 6 A-dependent manner, regulating cell migration and survival in colorectal cancer [ 49 ]. METTL14/IGF2BP2 prevents m 6 A-modified lncRNA ARHGAP5-AS1 degradation, playing an important part in hepatocellular carcinoma growth and metastasis [ 50 ]. IGF2BP2 functions as the m 6 A effector to stabilize E2F6 and E2F3, activating the Wnt/β-catenin pathway and facilitating liver tumor initiating cells (TICs) self-renewal and metastasis [ 51 ].…”

Exploring the role of m6A methylation regulators in glioblastoma multiforme and their impact on the tumor immune microenvironment

“…18 Recently, clinical trials have begun on GBM immunotherapy-related drugs which demonstrate durable antitumor activity with acceptable adverse reactions, suggesting that GBM TIME deserves further investigation. 19 Furthermore, m6A methylation promotes or suppresses a variety of tumor pathologies, [20][21][22] but studies on its relationship with GBM are lacking. Therefore, it is intriguing to examine the role of m6A regulators in GBM and their impact on the infiltration of the TIME in GBM.…”

CSDE1: a versatile regulator of gene expression in cancer

“…In fact, autoregulatory feed-back of RBPs is relatively frequent, attesting to their important functions in the cell ( 81 ). Regarding protein turnover, an interesting mechanism has been recently reported in hepatocellular carcinoma cells ( 82 ). Adenosine methylation (m 6 A) leads to stabilization of the lncRNA ARHGAP5-AS1 which, in turn, binds to CSDE1 and attenuates its interaction with the E3 ubiquitin ligase TRIM28, ultimately leading to reduced CSDE1 proteasomal degradation (Figure 5F ).…”