Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer.
Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer.
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通过靶向 PTEN 或 SPOP 突变前列腺癌中的 HDAC3 双重抑制 AKT-mTOR 和 AR 信号传导
DOI：
10.15252/emmm.201708478
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发表时间：
2018-04
影响因子：
11.1
通讯作者：
Huang H
中科院分区：
文献类型：
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作者：
Yan Y;An J;Yang Y;Wu D;Bai Y;Cao W;Ma L;Chen J;Yu Z;He Y;Jin X;Pan Y;Ma T;Wang S;Hou X;Weroha SJ;Karnes RJ;Zhang J;Westendorf JJ;Wang L;Chen Y;Xu W;Zhu R;Wang D;Huang H
由于频繁的 PTEN 缺失或 SPOP 突变，AKT-mTOR 和雄激素受体 (AR) 信号通路在前列腺癌中异常激活。临床障碍是，针对其中之一往往会激活另一个。在这里，我们证明 HDAC3 增强前列腺癌细胞中的 AKT 磷酸化，并且其过度表达与患者样本中的 AKT 磷酸化相关。 HDAC3 促进赖氨酸 63 链多泛素化和 AKT 磷酸化，这种作用是通过 AKT 赖氨酸 14 和 20 残基的脱乙酰化以及 HDAC3 与支架蛋白 APPL1 的相互作用介导的。在 Pten 敲除小鼠模型中，条件性纯合性 Hdac3 缺失通过同时阻断 AKT 和 AR 信号传导来抑制前列腺肿瘤的发生和进展。使用选择性 HDAC3 抑制剂 RGFP966 对 HDAC3 进行药理学抑制，可抑制培养物、患者来源的类器官和小鼠异种移植物中 PTEN 缺陷和 SPOP 突变的前列腺癌细胞的生长。我们的研究确定 HDAC3 是 AKT 和 AR 信号传导的常见上游激活剂，并揭示在前列腺癌中通过单药靶向 HDAC3 可以实现 AKT 和 AR 通路的双重抑制。
AKT‐mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN‐deficient and SPOP‐mutated prostate cancer cells in culture, patient‐derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single‐agent targeting of HDAC3 in prostate cancer.