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

  • Exp Hematol Oncol. 2023 Jan 6;12(1):1. doi: 10.1186/s40164-022-00370-2.
Weijian Wang  #  1  2 ,  Qibo Huang  #  1  2 ,  Zhibin Liao  #  1  2  3 ,  Hongwei Zhang  1  2  3 ,  Yachong Liu  1  2 ,  Furong Liu  1  2 ,  Xiaoping Chen  1  2  3 ,  Bixiang Zhang  1  2  3 ,  Yan Chen  4  5  6 ,  Peng Zhu  7  8  9
Affiliations
  • 1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China.
  • 3. Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 4. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].
  • 5. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China. [email protected].
  • 6. Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].
  • 7. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].
  • 8. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China. [email protected].
  • 9. Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].
  • # Contributed equally.
PMID: 36609413 DOI: 10.1186/s40164-022-00370-2
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.

Keywords
AKT; ALKBH5; HCC; Methylation; PAQR4.
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