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.
Highlights
Prostate cancer (PC) is the second most commonly diagnosed malignancy in men worldwide [1, 2]
Co-immunoprecipitation and immunoprecipitaion Subconfluent proliferating cells in 100-cm2 dishes were harvested, antibodies showed that the expression of KAT2A was higher in tissues from patients with high-risk PC (Fig. 1F)
Considering that these results suggested that KAT2A plays a critical role in PC, we determined KAT2A expression levels in these two cell lines and found that KAT2A expression was up-regulated in C4-2-AbiR cells suspended in 100 μl of serum-free medium were injected subcutaneously into the armpit on the right side of the mice
Summary
Prostate cancer (PC) is the second most commonly diagnosed malignancy in men worldwide [1, 2]. Cells were maintained in RPMI 1640 medium (Hyclone, GE Healthcare Life Sciences, Logan, UT, USA) with 10% foetal bovine serum (Biologic Industries, Kibbutz Beit Haemek, Israel) that contained 1% penicillin/streptomycin (Beyotime Institute of Biotechnology, Nanjing, China) at 37 °C in 5% CO2 and 95% humidified air. Immunoreactivity was scored based on a combination of both the percentage and intensity of positively stained tumour cells to generate an Establishment of the abiraterone-resistant cell line C4-2-AbiR The starting treatment concentration of abiraterone acetate (MedChemExpress, NJ 08852, USA) in the parental C4-2 cell culture medium was 0.5 μM. At this concentration, the cells were stably passaged three times. C4-2 and LNCaP were infected with lentivirus overexpressing KAT2A (Hanheng Biotechnology, Shanghai, China)
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