Acetate utilization promotes hormone therapy resistance in prostate cancer through neuroendocrine differentiation
Dajun Gao, Yanting Shen, Lingfan Xu, Yi Sun, Hailiang Hu, Bin Xu, Zhong Wang, Huan Xu
Abstract
Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC). We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies. The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume. Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC. • Acetate level and ACSS2 expression were elevated during prolonged hormone therapy in patients with PCa. • Elevated acetate concentrations and ACSS2 expression led to neuroendocrine differentiation-induced hormone therapy resistance. • ACSS2 overexpression acetylated the promoter of c-Myc that enhanced its expression. • ACSS2 inhibitors, in combination with hormone therapy, significantly reduced the volume of PCa tumors.