ALKBH5 exacerbates early cardiac damage after radiotherapy for breast cancer via m6A demethylation of TLR4.

Abstract

Radiotherapy is an important cancer treatment for breast cancer patients, improving overall survival; however, it can lead to a common complication, radiation-induced heart disease (RIHD). N6-methyladenosine (m6A) RNA modification plays a critical role in the regulation of myocardial function. The aim of this study is to investigate the effect of m6A modification on cardiac injury following radiotherapy for breast cancer. Cardiac dysfunction was assessed by echocardiography and hematoxylin and eosin staining. The expression of ALKBH5 was analyzed by quantitative real-time PCR, western blot, and immunohistochemistry. The underlying mechanism was investigated using methylated RNA immunoprecipitation (MeRIP), RIP, and dual-luciferase reporter assays. The results showed that in RIHD, ALKBH5 expression was upregulated in breast cancer patients after radiotherapy and in RIHD mouse models. ALKBH5 downregulated the m6A modification level of Toll-like receptor 4 (TLR4). Overexpression of TLR4 abolished the inhibitory effect of ALKBH5 silencing on RIHD in mice. In summary, this study revealed a novel regulatory mechanism of ALKBH5-mediated m6A demethylation in RIHD, which could provide a promising therapeutic strategy for cardiac dysfunction following radiotherapy in breast cancer patients.