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.
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KAT2A介导的AR易位入核促进去势抵抗性前列腺癌的阿比特龙抵抗
DOI：
10.1038/s41419-021-04077-w
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发表时间：
2021-08-12
影响因子：
9
通讯作者：
Xing Y
中科院分区：
文献类型：
--
作者：
Lu D;Song Y;Yu Y;Wang D;Liu B;Chen L;Li X;Li Y;Cheng L;Lv F;Zhang P;Xing Y
阿比特龙是一种新型雄激素合成抑制剂，已被批准用于去势抵抗性前列腺癌（CRPC）的治疗。然而，大多数患者最终获得耐药性，这种耐药性的相关机制仍然在很大程度上未阐明。赖氨酸乙酰转移酶2A（KAT 2A）通过雄激素受体（AR）的乙酰化和翻译后修饰增强某些组蛋白或非组蛋白蛋白的转录活性。因此，我们假设KAT 2A可能在前列腺肿瘤对激素治疗的抵抗中起关键作用。在这项研究中，我们发现KAT 2A的表达增加阿比特龙耐药的前列腺癌C4-2细胞（C4-2-AbiR）。一致的是，在前列腺癌根治术后表现出高级别疾病或生化复发的患者以及临床生存结局较差的患者中观察到KAT 2A表达升高。此外，KAT 2A敲低部分地使C4-2-AbiR细胞对阿比特龙重新敏感，而KAT 2A过表达促进亲本C4-2细胞中的阿比特龙抗性。与这一发现一致，KAT 2A敲除可以挽救小鼠模型中阿比特龙的敏感性并抑制C4-2-AbiR细胞的增殖。在机制上，KAT 2A直接乙酰化AR的铰链区，并诱导AR从细胞质易位到细胞核，导致AR靶向基因前列腺特异性抗原（PSA）的转录活性增加，从而导致对阿比特龙对增殖的抑制作用的抗性。综上所述，我们的研究结果表明，KAT 2A在调节影响CRPC发展的AR翻译后修饰中具有重要作用，这表明靶向KAT 2A可能是CRPC治疗的潜在策略。
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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前列腺癌的基因表达谱揭示了多个分子途径在转移过程中的参与。
影响因子：
3.8
作者：
Chandran, Uma R.;Ma, Changqing;Dhir, Rajiv;Bisceglia, Michelle;Lyons-Weiler, Maureen;Liang, Wenjing;Michalopoulos, George;Becich, Michael;Monzon, Federico A.
通讯作者：
Monzon, Federico A.
影响因子：
16.6
作者：
Fournier, Marjorie;Orpinell, Meritxell;Grauffel, Cedric;Scheer, Elisabeth;Garnier, Jean-Marie;Ye, Tao;Chavant, Virginie;Joint, Mathilde;Esashi, Fumiko;Dejaegere, Annick;Gonczy, Pierre;Tora, Laszlo
通讯作者：
Tora, Laszlo
影响因子：
11.2
作者：
Li, Shangze;Fong, Ka-wing;Yu, Jindan
通讯作者：
Yu, Jindan
靶向 KIF4A/AR 轴逆转去势抵抗性前列腺癌的内分泌治疗抵抗
影响因子：
11.5
作者：
Cao, Qi;Song, Zhengshuai;Zhang, Xiaoping
通讯作者：
Zhang, Xiaoping
影响因子：
4.8
作者：
Gaughan, L;Logan, IR;Robson, CN
通讯作者：
Robson, CN