Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), mak-ing E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing onco-transcript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat -shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulat-ing E7 mRNA-IGF2BP1 oncogenic complex.
基金：
National Key R&D Program of China [2021YFC2700903]; China Postdoctoral Science Foundation [2021M702877]; Key Technology R&D Program of China [2019YFC1005204]; National Natural Science Foundation of China [31972883, 81872942]
通讯机构：[1]Zhejiang Univ, Womens Hosp, Inst Genet, Sch Med, Hangzhou 310006, Peoples R China[2]Zhejiang Univ, Dept Environm Med, Sch Med, Hangzhou 310006, Peoples R China[4]Zhejiang Univ, Affiliated Hosp 1, Dept Hematol, Sch Med, Hangzhou 310058, Peoples R China[5]Zhejiang Univ, Dept Publ Hlth, Sch Med, Hangzhou 310058, Peoples R China[9]Zhejiang Univ, Canc Ctr, Hangzhou 310006, Peoples R China
推荐引用方式(GB/T 7714)：
Wang Lingfang,Zhan Guankai,Maimaitiyiming Yasen,et al.m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress[J].CELL REPORTS.2022,41(3):doi:10.1016/j.celrep.2022.111546.
APA：
Wang, Lingfang,Zhan, Guankai,Maimaitiyiming, Yasen,Su, Yingfeng,Lin, Shitong...&Hsu, Chih-Hung.(2022).m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress.CELL REPORTS,41,(3)
MLA：
Wang, Lingfang,et al."m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress".CELL REPORTS 41..3(2022)
生物学