Login / Signup

O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N 6 -methyladenosine-dependent manner.

Yang YangYu YanJiaxin YinNi TangKai WangLu-Yi HuangJie HuZhongqi FengQingzhu GaoAi-Long Huang
Published in: Signal transduction and targeted therapy (2023)
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), but its pathogenic mechanism remains to be explored. The RNA N 6 -methyladenosine (m 6 A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), plays a critical role in the HCC progression. However, the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive. Here, we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection. O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination. Mechanistically, YTHDF2 stabilized minichromosome maintenance protein 2 (MCM2) and MCM5 transcripts in an m 6 A-dependent manner, thus promoting cell cycle progression and HBV-related HCC tumorigenesis. Moreover, targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression. Taken together, our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m 6 A methylation and HCC progression. Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.
Keyphrases
  • hepatitis b virus
  • liver failure
  • cell cycle
  • risk factors
  • cell proliferation
  • transcription factor
  • signaling pathway
  • risk assessment
  • amino acid
  • binding protein
  • human health