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

• Published in: Experimental hematology & oncology Vol. 12; no. 1; p. 1
• Main Authors: Wang, Weijian, Huang, Qibo, Liao, Zhibin, Zhang, Hongwei, Liu, Yachong, Liu, Furong, Chen, Xiaoping, Zhang, Bixiang, Chen, Yan, Zhu, Peng
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.01.2023; BioMed Central; BMC
• Subjects: AKT; ALKBH5; Cancer; Development and progression; Genetic aspects; Genetic transcription; HCC; Methylation; Methyltransferases; PAQR4; RNA; China; HCC; ALKBH5; AKT; PAQR4; Methylation
• ISSN: 2162-3619; 2162-3619
• DOI: 10.1186/s40164-022-00370-2

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. 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. ALKBH5 inhibits HCC growth by downregulating PAQR4 expression in an m6A-dependent manner, therefore suppressing PI3K/AKT pathway activation.