ALKBH5通过YTHDF1/IGF2BP2介导的方式靶向TLR2促进下咽鳞状细胞癌凋亡。

ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

作者信息

Ye Jing, Wu Yuting, Chen Yao, Ren Yiyue, Jiang Xiaohua, Dong Zhihuai, Zhang Jingna, Jin Mao, Chen Xiaozhen, Wang Zhanggui, Xiao Mang

机构信息

Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang `University, Hangzhou, Zhejiang, China.

Department of Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

出版信息

Cell Death Discov. 2023 Aug 23;9(1):308. doi: 10.1038/s41420-023-01589-6.

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (mA) RNA modification occurs in HPSCC. The expression of the mA demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferation by regulating human Toll-like receptor 2 (TLR2) in an mA-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 mA modification, which could be recognized by the mA readers IGF2BP2 and YTHDF1. IGF2BP2 facilitates TLR2 mRNA stability, whereas YTHDF1 promotes TLR2 mRNA translation. The current work uncovered a critical function of ALKBH5 in TLR2 regulation and provides a novel role for mA demethylation of mRNA in HPSCC. The inhibition of mA modification of ALKBH5 in HPSCC deserves further clinical investigation.

下咽鳞状细胞癌（HPSCC）是最具侵袭性的癌症之一，其预后极差，声名狼藉。然而，进行的分子生物学研究非常少。作为一种表观遗传基因调控的新方法，N6-甲基腺苷（m⁶A）RNA修饰存在于HPSCC中。m⁶A去甲基化酶AlkB同源物5（ALKBH5）的表达在人类HPSCC中经常下调。此外，我们发现ALKBH5在HPSCC细胞中以m⁶A依赖的方式通过调节人类Toll样受体2（TLR2）来损害细胞增殖。ALKBH5降低了TLR2的m⁶A修饰，这可以被m⁶A阅读蛋白IGF2BP2和YTHDF1识别。IGF2BP2促进TLR2 mRNA的稳定性，而YTHDF1促进TLR2 mRNA的翻译。目前的工作揭示了ALKBH5在TLR2调控中的关键作用，并为HPSCC中mRNA的m⁶A去甲基化提供了新的作用。HPSCC中ALKBH5的m⁶A修饰抑制值得进一步的临床研究。