ALKBH5通过以m6A依赖的方式对PAQR4进行转录后抑制来阻止肝细胞癌进展。
ALKBH5 prevents hepatocellular carcinoma progression by post-transcriptional inhibition of PAQR4 in an m6A dependent manner.
作者信息
Wang Weijian, Huang Qibo, Liao Zhibin, Zhang Hongwei, Liu Yachong, Liu Furong, Chen Xiaoping, Zhang Bixiang, Chen Yan, Zhu Peng
机构信息
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China.
出版信息
Exp Hematol Oncol. 2023 Jan 6;12(1):1. doi: 10.1186/s40164-022-00370-2.
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.
背景
N6-甲基腺苷（m6A）是一种普遍存在的mRNA修饰，已知在多种癌症的肿瘤发生中发挥重要作用。N6-甲基腺苷（m6A）RNA甲基化的功能取决于多种甲基转移酶和去甲基酶。 AlkB同源物5（ALKBH5）是一种去甲基酶，其生物学功能在肝癌中尚未得到充分研究。
结果
ALKBH5在肝癌细胞中表达下调并具有抗肿瘤作用。此外，基于转录组测序和验证研究，孕激素和脂联素受体4（PAQR4）被确定为ALKBH5的下游靶点。我们发现ALKBH5以N6-甲基腺苷（m6A）依赖的方式降低PAQR4 mRNA和蛋白表达。该研究还表明，ALKBH5通过m6A阅读蛋白IGF2BP1改变PAQR4的表达。在体内和体外实验中，PAQR4均与肝癌的发生发展密切相关。最后，我们发现PAQR4与AKT相互作用并增强PI3K/AKT信号通路的激活。
结论
ALKBH5通过以m6A依赖的方式下调PAQR4表达来抑制肝癌生长，从而抑制PI3K/AKT信号通路的激活。
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