Data from Hepatitis B Virus–Mediated m6A Demethylation Increases Hepatocellular Carcinoma Stemness and Immune Escape

Abstract

<div>Abstract<p>Hepatitis B viral (HBV) persistent infection plays a significant role in hepatocellular carcinoma (HCC) tumorigenesis. Many studies have revealed the pivotal roles of N6-methyladenosine (m6A) in multiple cancers, while the regulatory mechanism in stemness maintenance of HBV persistent infection-related HCC remains elusive. Here, we demonstrated that the level of m6A modification was downregulated by HBV in HBV-positive HCC, through enhanced stability of ALKBH5 mRNA. More specifically, we also identified that ALKBH5 mRNA was functionally required for the stemness maintenance and self-renewal in the HBV-positive HCC, but dispensable in HBV-negative HCC. Mechanistically, ALKBH5 demethylated the m6A modification in the 3′ untranslated region of the oncogenic gene <i>SNAI2</i> to prevent the recognition of YTHDF2 therewith stabilize <i>SNAI2</i> transcripts, contributing to cancer stem cell traits in HBV-positive HCC. Moreover, the expression of <i>SNAI2</i> reversed the suppression of stemness properties by knocking down ALKBH5. In addition, ALKBH5/SNAI2 axis accelerates tumor immune evasion through activated ligand of immune checkpoint CD155. Our study unveiled that the ALKBH5 induces m6A demethylation of the <i>SNAI2</i> as a key regulator in HBV-related HCC, and identifies the function of ALKBH5/SNAI2/YTHDF2 axis in promoting the stem-like cells phenotype and immune escape during HBV infection.</p>Implications:<p>HBV promotes HCC stemness maintenance through elevate m6A modification of SNAI2 in an ALKBH5-YTHDF2–dependent manner and increases the expression of the ligand of immune checkpoint CD155.</p></div>