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
  • 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: [email protected].
  • 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: [email protected].
  • 12. Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address: [email protected].
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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