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

doi:10.1016/j.celrep.2022.111546

m⁶A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress

Cell Rep. 2022 Oct 25;41(4):111546. doi: 10.1016/j.celrep.2022.111546.

Authors

Lingfang Wang¹, Guankai Zhan², Yasen Maimaitiyiming³, Yingfeng Su², Shitong Lin⁴, Jinfeng Liu², Kunhui Su², Jiebo Lin², Shizhen Shen⁵, Wentao He², Fenfen Wang⁵, Jiafeng Chen², Siqi Sun², Yite Xue⁵, Jiaxin Gu⁵, Xiaojing Chen⁵, Jian Zhang², Lu Zhang⁶, Qianqian Wang⁷, Kao-Jung Chang⁸, Shih-Hwa Chiou⁸, Mikael Björklund⁹, Hua Naranmandura¹⁰, Xiaodong Cheng¹¹, Chih-Hung Hsu¹²

Affiliations

¹ Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
² Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China.
³ Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China; Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, and MOE Frontier Science Center for Brain Science and Brain-machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁵ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
⁶ Cancer Center, Zhejiang University, Hangzhou 310006, China.
⁷ Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310006, China.
⁸ Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
⁹ Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, Zhejiang 314499, China.
¹⁰ Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310006, China. Electronic address: narenman@zju.edu.cn.
¹¹ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address: chengxd@zju.edu.cn.
¹² Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address: ch_hsu@zju.edu.cn.

PMID: 36288717
DOI: 10.1016/j.celrep.2022.111546

Abstract

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.

Keywords: CP: Cancer; CP: Molecular biology; HPV; N6-methyladenosine; cervical cancer; heat stress; human papillomavirus E7 oncotranscripts; hyperthermia; m6A; m6A reader IGF2BP1; phase separation; protein degradation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alphapapillomavirus* / metabolism
Carcinogenesis
Heat-Shock Proteins
Heat-Shock Response
Humans
Papillomaviridae
Papillomavirus E7 Proteins / genetics
Papillomavirus E7 Proteins / metabolism
Papillomavirus Infections*
Proteasome Endopeptidase Complex
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Viral / genetics
RNA-Binding Proteins
Ubiquitin

Substances

Heat-Shock Proteins
Papillomavirus E7 Proteins
Proteasome Endopeptidase Complex
RNA, Messenger
RNA, Viral
Ubiquitin
RNA-Binding Proteins