The HDAC inhibitor LBH589 induces ERK-dependent prometaphase arrest in prostate cancer via HDAC6 inactivation and down-regulation.
The HDAC inhibitor LBH589 induces ERK-dependent prometaphase arrest in prostate cancer via HDAC6 inactivation and down-regulation.
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DOI：
10.1371/journal.pone.0073401
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cha TL
中科院分区：
文献类型：
--
作者：
Chuang MJ;Wu ST;Tang SH;Lai XM;Lai HC;Hsu KH;Sun KH;Sun GH;Chang SY;Yu DS;Hsiao PW;Huang SM;Cha TL
组蛋白去乙酰化酶抑制剂（HDACIs）在多种癌症模型中具有有效的抗癌活性。在临床应用HDACI之前，需要了解HDACI治疗反应性的分子机制。本研究旨在确定一种有效的HDACI LBH589 （Panobinostat）是否对LNCaP和PC-3前列腺癌（PCa）细胞具有不同的治疗反应性。LBH589处理后，前者表现为前期阻滞，随后发生凋亡，而后者则不那么敏感，出现晚期G2阻滞。LBH589治疗下调了HDAC6和持续的ERK激活，并促进了中期阻滞。机制上，LBH589抑制HDAC6活性，使其与蛋白磷酸酶PP1α分离，增加14-3-3ζ乙酰化。乙酰化14-3-3ζ被PP1α去磷酸化后，对c-Raf的第259位丝氨酸和Cdc25C的第216位丝氨酸释放掩膜效应，导致ERK活化。LBH589增强ERK活性，进一步下调HDAC6蛋白水平，并通过自由正向调控维持ERK激活。Cdc25C和ERK的持续激活在最敏感的LNCaP细胞中导致早期m期（前期）阻滞和随后的凋亡，而在PC-3细胞中则没有。本研究提供了临床前证据，HDAC6可作为HDACI LBH589治疗前列腺癌的敏感治疗靶点进行临床转化。本研究还提出了HDAC6参与调节c-Raf-PP1-ERK信号通路和促进M期细胞周期转变的新机制。
Histone deacetylase inhibitors (HDACIs) have potent anti-cancer activity in a variety of cancer models. Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application. This study aimed to determine if a potent HDACI, LBH589 (Panobinostat), had differential therapeutic responsiveness towards LNCaP and PC-3 prostate cancer (PCa) cells. The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment, while the latter was less sensitive and had late G2 arrest. The LBH589 treatment down-regulated HDAC6 and sustained ERK activation, and contributed to prometaphase arrest. Mechanistically, LBH589 inhibited HDAC6 activity, caused its dissociation from protein phosphatase PP1α, and increased 14-3-3ζ acetylation. Acetylated 14-3-3ζ released its mask effect on serine 259 of c-Raf and serine 216 of Cdc25C subsequent to de-phosphorylation by PP1α, which contributed to ERK activation. Enhanced ERK activity by LBH589 further down-regulated HDAC6 protein levels and sustained ERK activation by free-forward regulation. The sustained Cdc25C and ERK activation resulted in early M-phase (prometaphase) arrest and subsequent apoptosis in the most sensitive LNCaP cells but not in PC-3 cells. This study provides pre-clinical evidence that HDAC6 may serve as a sensitive therapeutic target in the treatment of prostate cancer with HDACI LBH589 for clinical translation. This study also posits a novel mechanism of HDAC6 participation in regulating the c-Raf-PP1-ERK signaling pathway and contributing to M phase cell-cycle transition.
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影响因子：
--
作者：
Aldana-Masangkay GI;Sakamoto KM
通讯作者：
Sakamoto KM
影响因子：
10.5
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
Sladek, R
影响因子：
3.7
作者：
Lee, YJ;Cho, HN;Lee, YS
通讯作者：
Lee, YS