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:10.1186/s40164-022-00370-2

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.

Authors

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. c_yan66@yahoo.com.
⁵ Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China. c_yan66@yahoo.com.
⁶ Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. c_yan66@yahoo.com.
⁷ Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. zhupeng@tjh.tjmu.edu.cn.
⁸ Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China. zhupeng@tjh.tjmu.edu.cn.
⁹ Department of General Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. zhupeng@tjh.tjmu.edu.cn.

^# Contributed equally.

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.

Grants and funding

No.82103597/National Natural Science Foundation of China