Heat shock protein 70 regulates m6A modification in response to heat shock in esophageal squamous cell carcinoma.

Abstract

Heat shock has been known to induce hyperplasia in esophageal epithelial cells. It is widely considered as a crucial risk factor in the initiation and development of esophageal squamous cell carcinoma (ESCC), yet our understanding of the underlying mechanisms remains limited. The m6A modification of mRNA plays a role in mediating several cellular processes and is critical during cell stress. Our study revealed that inhibiting of m6A 'writer' components of ESCC cells exhibit higher death rates and slower recovery after heat shock. After normalization using mRNA expression profiles, 91.08 % of significantly changed m6A modifications aligned with corresponding mRNA abundance changes, with no evidence of over-modification, while the increase in m6A modification of 8.92 % of heat-shock associated genes far exceeded the increase in mRNA (hyper - m6A modification), and A/U rich motifs were commonly observed in the 3'UTR of these gene. Inside the nucleus, the binding of HSP70s in m6A writer complex promote the hyper - m6A modification in specific mRNAs after heat shock. The stronger nuclear localization of HSP70 in ESCC tissues correlates with a poor prognosis for the patients. In conclusion, our research revealed that the nuclear HSP70 protein could bind to the METTL3/14 writer complex and regulate mRNA's m6A modification. Our results provide a new perspective for research into how HSP70 protein regulates mRNA stability and suggests a new direction for the comprehensive prevention and treatment of ESCC.