m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress
Lingfang Wang, Guankai Zhan, Yasen Maimaitiyiming, Yingfeng Su, Shitong Lin, Jinfeng Liu, Kunhui Su, Jiebo Lin, Shizhen Shen, Wentao He, Fenfen Wang, Jiafeng Chen, Siqi Sun, Yite Xue, Jiaxin Gu, Xiaojing Chen, Jian Zhang, Lu Zhang, Qianqian Wang, Kao-Jung Chang, Shih-Hwa Chiou, Mikael Björklund, Hua Naranmandura, Xiaodong Cheng, Chih-Hung Hsu
Journal：Cell Reports
IF：10
DOI：10.1016/j.celrep.2022.111546
PMID：36288717
Published：2022-10-25
research field：肿瘤学分子生物学癌症生物学
Abstract
Summary Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N 6 -methyladenosine (m 6 A) and stabilized by IGF2BP1, a cellular m 6 A 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 m 6 A-modified E7 mRNA to form distinct heat-induced m 6 A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m 6 A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.
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