1. Academic Validation
  2. KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer

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

  • Cell Death Dis. 2021 Aug 12;12(8):787. doi: 10.1038/s41419-021-04077-w.
Dingheng Lu  # 1 Yarong Song  # 1 Ying Yu  # 1 Decai Wang 1 2 Bing Liu 1 Liang Chen 1 Xuexiang Li 1 Yunxue Li 1 Lulin Cheng 1 Fang Lv 1 Pu Zhang 1 Yifei Xing 3
Affiliations

Affiliations

  • 1 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. yfxing@hust.edu.cn.
  • # Contributed equally.
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 to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the Androgen Receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate Cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate Cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.

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