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, 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. [ABSTRACT FROM AUTHOR]