Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia, USA
Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
J Biol Chem. 2020 Jun 19;295(25):8550-8559. doi: 10.1074/jbc.RA120.013794. Epub 2020 May 6.
The transcriptional coactivator YAP1 (yes-associated protein 1) regulates cell proliferation, cell-cell interactions, organ size, and tumorigenesis. Post-transcriptional modifications and nuclear translocation of YAP1 are crucial for its nuclear activity. The objective of this study was to elucidate the mechanism by which the steroid hormone androgen regulates YAP1 nuclear entry and functions in several human prostate cancer cell lines. We demonstrate that androgen exposure suppresses the inactivating post-translational modification phospho-Ser-127 in YAP1, coinciding with increased YAP1 nuclear accumulation and activity. Pharmacological and genetic experiments revealed that intact androgen receptor signaling is necessary for androgen's inactivating effect on phospho-Ser-127 levels and increased YAP1 nuclear entry. We also found that androgen exposure antagonizes Ser/Thr kinase 4 (STK4/MST1) signaling, stimulates the activity of protein phosphatase 2A, and thereby attenuates the phospho-Ser-127 modification and promotes YAP1 nuclear localization. Results from quantitative RT-PCR and CRISPR/Cas9-aided gene knockout experiments indicated that androgen differentially regulates YAP1-dependent gene expression. Furthermore, an unbiased computational analysis of the prostate cancer data from The Cancer Genome Atlas revealed that YAP1 and androgen receptor transcript levels correlate with each other in prostate cancer tissues. These findings indicate that androgen regulates YAP1 nuclear localization and its transcriptional activity through the androgen receptor-STK4/MST1-protein phosphatase 2A axis, which may have important implications for human diseases such as prostate cancer.
转录共激活因子 YAP1（yes-associated protein 1）调节细胞增殖、细胞间相互作用、器官大小和肿瘤发生。YAP1 的转录后修饰和核转位对于其核活性至关重要。本研究的目的是阐明甾体激素雄激素调节几种人前列腺癌细胞系中 YAP1 核进入和功能的机制。我们证明雄激素暴露抑制了 YAP1 中具有失活作用的翻译后修饰磷酸化 Ser-127，同时伴随着 YAP1 核积累和活性增加。药理学和遗传学实验表明，完整的雄激素受体信号对于雄激素对磷酸化 Ser-127 水平的失活作用和增加的 YAP1 核进入是必要的。我们还发现，雄激素暴露拮抗丝氨酸/苏氨酸激酶 4（STK4/MST1）信号，刺激蛋白磷酸酶 2A 的活性，从而减弱磷酸化 Ser-127 修饰并促进 YAP1 核定位。定量 RT-PCR 和 CRISPR/Cas9 辅助基因敲除实验的结果表明，雄激素对 YAP1 依赖性基因表达进行差异调节。此外，对来自癌症基因组图谱的前列腺癌数据的无偏计算分析表明，前列腺癌组织中 YAP1 和雄激素受体转录本水平相互关联。这些发现表明，雄激素通过雄激素受体-STK4/MST1-蛋白磷酸酶 2A 轴调节 YAP1 的核定位及其转录活性，这可能对前列腺癌等人类疾病具有重要意义。
