KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer

• DOI: 10.1038/s41419-021-04077-w
• Publication Date: 2021-08-12T04:19:22Z
• Authors: Dingheng Lu; Yarong Song; Ying Yu; Decai Wang; Bing Liu; Liang Chen; Xuexiang Li; Yunxue Li; Lulin Cheng; Fang Lv; Pu Zhang; Yifei Xing
• Keywords: Abiraterone acetate; Histone acetyltransferase

Abstract Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) reported enhance transcriptional activity certain histone or non-histone proteins through acetylation post-translational modification of receptor (AR). Therefore, we hypothesised that KAT2A might play critical role in tumours hormonal In study, found expression was increased abiraterone-resistant C4-2 cells (C4-2-AbiR). Consistently, elevated observed with exhibiting high-grade disease biochemical recurrence following radical prostatectomy, as well those poor clinical survival outcomes. Moreover, knockdown partially re-sensitised C4-2-AbiR abiraterone, whereas overexpression promoted abiraterone parental cells. Consistent finding, rescued sensitivity inhibited proliferation mouse model. Mechanistically, directly acetylated hinge region AR, induced AR translocation from cytoplasm nucleus, resulting AR-targeted gene specific antigen (PSA) leading inhibitory effect on proliferation. Taken together, our findings demonstrate substantial regulation modifications affecting CRPC development, suggesting targeting be potential strategy