Experimental Hematology & Oncology (Jan 2023)

ALKBH5 prevents hepatocellular carcinoma progression by post-transcriptional inhibition of PAQR4 in an m6A dependent manner

  • Weijian Wang,
  • Qibo Huang,
  • Zhibin Liao,
  • Hongwei Zhang,
  • Yachong Liu,
  • Furong Liu,
  • Xiaoping Chen,
  • Bixiang Zhang,
  • Yan Chen,
  • Peng Zhu

DOI
https://doi.org/10.1186/s40164-022-00370-2
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 16

Abstract

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Abstract Background N6-methyladenosine (m6A) is a prevalent modification of mRNA and is known to play important roles in tumorigenesis in many types of cancer. The function of N6-methyladenosine (m6A) RNA methylation depends on a variety of methyltransferases and demethylases. AlkB homolog 5 (ALKBH5) is a demethylase, and its biological function has not been completely explored in HCC. Results ALKBH5 is downregulated and has antitumor effects in HCC cells. In addition, Progestin and AdipoQ Receptor 4 (PAQR4) was identified as a downstream target of ALKBH5 based on transcriptome sequencing and validation studies. We found that ALKBH5 decreases PAQR4 mRNA and protein expression in an N6-methyladenosine (m6A)-dependent manner. The study also showed that ALKBH5 changes PAQR4 expression via the m6A reader IGF2BP1. In both in vivo and in vitro experiments, PAQR4 showed a strong association with the development of HCC. Finally, we found that PAQR4 interacts with AKT and enhances PI3K/AKT pathway activation. Conclusions ALKBH5 inhibits HCC growth by downregulating PAQR4 expression in an m6A-dependent manner, therefore suppressing PI3K/AKT pathway activation.

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