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

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

doi:10.1038/s41420-023-01589-6

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

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

Authors

Jing Ye^#¹, Yuting Wu^#¹, Yao Chen², Yiyue Ren³, Xiaohua Jiang¹, Zhihuai Dong¹, Jingna Zhang¹, Mao Jin¹, Xiaozhen Chen⁴, Zhanggui Wang⁵, Mang Xiao⁶

Affiliations

¹ Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang `University, Hangzhou, Zhejiang, China.
² Department of Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ Department of Head and Neck Surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University Hangzhou, Zhejiang Province, China.
⁴ Central Laboratory, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University Hangzhou, Zhejiang Province, China. sochenxiaozhen@126.com.
⁵ Department of Radiotherapy, The Second People's Hospital of Anhui Province, Hefei, Anhui, China. wzg79@zju.edu.cn.
⁶ Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang `University, Hangzhou, Zhejiang, China. joelxm@zju.edu.cn.

^# Contributed equally.

Abstract

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 (m⁶A) RNA modification occurs in HPSCC. The expression of the m⁶A 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 m⁶A-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 m⁶A modification, which could be recognized by the m⁶A 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 m⁶A demethylation of mRNA in HPSCC. The inhibition of m⁶A modification of ALKBH5 in HPSCC deserves further clinical investigation.

Abstract

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