PFOA exposure promotes prostate cancer progression by enhancing autophagy through m6A modification of MAPK15 mRNA
Yongjing Qian, Zixuan Liu, Xinyi Lv, Xiaojing Cai, Jianfeng Wei, Ling Zhang, Xiannan Meng
Abstract
Perfluorooctanoic acid (PFOA) is a globally pervasive environmental contaminant characterized by chemical stability and bioaccumulation through the food chain, posing serious health risks to both humans and animals. Accumulating evidence has linked PFOA exposure to the development of various cancers, including prostate cancer (PCa), renal cancer, breast cancer, and ovarian cancer. However, the molecular mechanisms by which PFOA promotes PCa progression remain unclear. In this study, we demonstrate that low-dose PFOA exposure enhances the expression of mitogen-activated protein kinase 15 (MAPK15), thereby promoting autophagy and facilitating tumor cell proliferation. Mechanistically, PFOA binds to the N6-methyladenosine (m 6 A) demethylase FTO (fat mass and obesity-associated protein), inhibiting its demethylase activity and resulting in elevated m 6 A modification levels on MAPK15 mRNA. This modification leads to increased MAPK15 protein expression, which in turn activates autophagy pathways and drives the proliferation, migration, and invasion of PCa cell lines. Collectively, our findings provide critical molecular evidence for the carcinogenic potential of PFAS compounds and offer new insights into environmental toxicology and ecological risk assessment. • PFOA exposure alters m 6 A RNA modification for the first time in prostate cancer cells. • PFOA inhibits FTO activity, leading to increased MAPK15 expression. • PFOA induces autophagy and promotes progression of prostate cancer.