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

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.
Lingfang Wang 1,  Guankai Zhan 2,  Yasen Maimaitiyiming 3,  Yingfeng Su 2,  Shitong Lin 4,  Jinfeng Liu 2,  Kunhui Su 2,  Jiebo Lin 2,  Shizhen Shen 5,  Wentao He 2,  Fenfen Wang 5,  Jiafeng Chen 2,  Siqi Sun 2,  Yite Xue 5,  Jiaxin Gu 5,  Xiaojing Chen 5,  Jian Zhang 2,  Lu Zhang 6,  Qianqian Wang 7,  Kao-Jung Chang 8,  Shih-Hwa Chiou 8,  Mikael Björklund 9,  Hua Naranmandura 10,  Xiaodong Cheng 11,  Chih-Hung Hsu 12
Affiliations

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.

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