Gene

Methyltransferase

Hepatocellular carcinoma

Biology

Messenger RNA

Ubiquitin ligase

Long non-coding RNA

Cancer research

Ubiquitin

Genetics

Antisense RNA

Methylation

Gene knockdown

N6-Methyladenosine

Clinical and Translational Medicine

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, N 6 ‐methyladenosine (m 6 A) regulates gene expression by impacting multiple aspects of mRNA metabolism. However, there are still no reports on genome‐wide screening and functional annotation of m 6 A‐methylated lncRNAs in HCC. Methods The m 6 A 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 m 6 A‐seq data of HCC cells, we identified 22 candidate lncRNAs with evidently dysregulated m 6 A levels. Among these lncRNAs, we found that ARHGAP5‐AS1 is the lncRNA with the highest levels of m 6 A modification and significantly increased expression in HCC specimens. METTL14 acts as the m 6 A writer of ARHGAP5‐AS1 and IGF2BP2 stabilises the lncRNA as its m 6 A 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 m 6 A‐modified lncRNAs controlling CSDE1‐mediated oncogenic RNA regulons and highlights lncRNAs as potential targets for future therapeutics against HCC.

N<sup>6</sup>‐methyladenosine‐modified lncRNA ARHGAP5‐AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma

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

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