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6-Methyladenosine Modification Confers Thermal Vulnerability to HPV E7 Oncotranscripts via Reverse Regulation of Its Reader Protein IGF2BP1 Upon Heat Stress
Zhejiang University - Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s Hospital; Huazhong University of Science and Technology - Department of Gynecologic Oncology
Human Papillomavirus (HPV) induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here we report that E7 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 downregulated E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins, and reversed HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promoted IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat induced m6A E7 mRNA-IGF2BP1 granules, which were resolved by the ubiquitin-proteasome system. Collectively, our results not only uncover a novel mutual regulation between m6A RNA and its reader but also provide a heat treatment-involved therapeutic strategy for HPV associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.
Keywords: Human papillomavirus, N6-methyladenosine, Heat stress, E7 oncoprotein, IGF2BP1
Wang, Lingfang and Zhan, Guankai and Maimaitiyiming, Yasen and Su, Yingfeng and Lin, Jiebo and Shen, Shizhen and He, Wentao and Liu, Jingfeng and Wang, Fenfen and Xue, Yite and Su, Kunhui and Chen, Xiaojing and Zhang, Jian and Wang, Qianqian and Chang, Kao-Jung and Chiou, Shih-Hwa and Björklund, Mikael and Naranmandura, Hua and Cheng, Xiaodong and Hsu, Chih-Hung, N
6-Methyladenosine Modification Confers Thermal Vulnerability to HPV E7 Oncotranscripts via Reverse Regulation of Its Reader Protein IGF2BP1 Upon Heat Stress. Available at SSRN: https://ssrn.com/abstract=4046139 or http://dx.doi.org/10.2139/ssrn.4046139
This version of the paper has not been formally peer reviewed.
Zhejiang University - Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s Hospital ( email )
Zhejiang University - Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s Hospital ( email )
Zhejiang University - Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s Hospital ( email )
Zhejiang University - Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s Hospital ( email )
Zhejiang University - Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases Women’s Hospital ( email )
Hangzhou, 310006 China
Huazhong University of Science and Technology - Department of Gynecologic Oncology ( email )
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