Coactivator MYST1 Regulates Nuclear Factor-κB and Androgen Receptor Functions During Proliferation of Prostate Cancer Cells
Coactivator MYST1 Regulates Nuclear Factor-κB and Androgen Receptor Functions During Proliferation of Prostate Cancer Cells
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DOI：
10.1210/me.2014-1055
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发表时间：
2014-06-01
影响因子：
--
通讯作者：
Mujtaba, Shiraz
中科院分区：
文献类型：
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作者：
Jaganathan, Anbalagan;Chaurasia, Pratima;Mujtaba, Shiraz
在前列腺癌（PCa）中，雄激素受体（AR）和核因子-κ B（NF-κ B）之间的功能协同作用使对治疗方案的抗性升级并促进侵袭性肿瘤生长。虽然其潜在的机制尚不清楚，但辅激活因子的基因调控能力可以桥接AR和NF-κ B B的转录功能。本研究表明MYST 1（MOZ、YBF 2和SAS 2以及TIP 60蛋白1）共刺激PCa细胞中的AR和NF-κ B功能。我们证明NF-κ B的激活促进了MYST 1通过沉默调节蛋白1的脱乙酰化。此外，MYST 1与沉默调节蛋白1与AR的相互排斥作用调节组蛋白H4上赖氨酸16的乙酰化。值得注意的是，在AR缺乏的PC 3细胞和AR耗尽的LNCaP细胞中，MYST 1的减少激活了聚（ADP-核糖）聚合酶和半胱天冬酶3的切割，导致细胞凋亡。相反，在AR转化的PC 3细胞（PC 3-AR）中，MYST 1的缺失诱导细胞周期蛋白依赖性激酶（CDK）N1 A/p21，导致G（2）M阻滞。同时，磷酸化视网膜母细胞瘤、E2 F1、CDK 4和CDK 6的水平降低。最后，肿瘤蛋白D52（TPD 52）的表达在PC 3、PC 3-AR和LNCaP细胞中受到明确影响。综上所述，本研究的结果表明MYST 1与AR和NF-κ B的功能相互作用对于PCa进展至关重要。
In prostate cancer (PCa), the functional synergy between androgen receptor (AR) and nuclear factor-kappa B (NF-kappa B) escalates the resistance to therapeutic regimens and promotes aggressive tumor growth. Although the underlying mechanisms are less clear, gene regulatory abilities of coactivators can bridge the transcription functions of AR and NF-kappa B. The present study shows that MYST1 (MOZ, YBF2 and SAS2, and TIP60 protein 1) costimulates AR and NF-kappa B functions in PCa cells. We demonstrate that activation of NF-kappa B promotes deacetylation of MYST1 by sirtuin 1. Further, the mutually exclusive interactions of MYST1 with sirtuin 1 vs AR regulate the acetylation of lysine 16 on histone H4. Notably, in AR-lacking PC3 cells and in AR-depleted LNCaP cells, diminution of MYST1 activates the cleavage of poly(ADP-ribose) polymerase and caspase 3 that leads to apoptosis. In contrast, in AR-transformed PC3 cells (PC3-AR), depletion of MYST1 induces cyclin-dependent kinase (CDK) N1A/p21, which results in G(2)M arrest. Concomitantly, the levels of phospho-retinoblastoma, E2F1, CDK4, and CDK6 are reduced. Finally, the expression of tumor protein D52 (TPD52) was unequivocally affected in PC3, PC3-AR, and LNCaP cells. Taken together, the results of this study reveal that the functional interactions of MYST1 with AR and NF-kappa B are critical for PCa progression.