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

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,...

Full description

Saved in:
Bibliographic Details
Published in:Cell reports (Cambridge) 2022-10, Vol.41 (4), p.111546-111546, Article 111546
Main Authors: Wang, Lingfang, Zhan, Guankai, Maimaitiyiming, Yasen, Su, Yingfeng, Lin, Shitong, Liu, Jinfeng, Su, Kunhui, Lin, Jiebo, Shen, Shizhen, He, Wentao, Wang, Fenfen, Chen, Jiafeng, Sun, Siqi, Xue, Yite, Gu, Jiaxin, Chen, Xiaojing, Zhang, Jian, Zhang, Lu, Wang, Qianqian, Chang, Kao-Jung, Chiou, Shih-Hwa, Björklund, Mikael, Naranmandura, Hua, Cheng, Xiaodong, Hsu, Chih-Hung
Format: Article
Language:English
Subjects:
cervical cancer
heat stress
HPV
human papillomavirus E7 oncotranscripts
hyperthermia
m6A
m6A reader IGF2BP1
N6-methyladenosine
phase separation
protein degradation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •m6A-modified E7 transcripts are stabilized by the m6A reader IGF2BP1•Heat treatment downregulates E7 mRNA levels by destabilizing IGF2BP1•m6A-modified E7 reversely regulates the fate of its reader IGF2BP1 upon heat•Mild daily heat treatment suppresses E7-mediated malignancy of HPV-positive cells Wang et al. show that heat treatment selectively destabilizes an m6A-dependent HPV E7 mRNA-IGF2BP1 oncogenic complex. Their results identify thermal vulnerability of the E7 mRNA-IGF2BP1 complex as a targetable susceptibility in HPV-associated cancers and highlight a role of m6A RNA in regulating the fate of its reader.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.111546