N 6-Methyladenosine Modification Confers Thermal Vulnerability to HPV E7 Oncotranscripts via Reverse Regulation of Its Reader Protein IGF2BP1 Upon Heat Stress
N 6-Methyladenosine Modification Confers Thermal Vulnerability to HPV E7 Oncotranscripts via Reverse Regulation of Its Reader Protein IGF2BP1 Upon Heat Stress
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作者：
Wang Lingfang;Zhan Guankai;Maimaitiyiming Yasen（亚森·买买提依明，共同一作）;Su Yingfeng;Lin Jiebo;Shen Shizhen;He Wentao;Liu Jingfeng;Wang Fenfen;Xue Yite;Su Kunhui;Chen Xiaojing;Zhang Jian;Wang Qianqian;Chang Kao-Jung;Chiou Shih-Hwa;Mikael Björklund;Naranmandura Hua;
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 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 downregulating E7 mRNA-IGF2BP1 oncogenic complex.
