Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Department of Urology, West China Hospital, Sichuan University, Chengdu, China.
Cancer Sci. 2021 Feb;112(2):691-702. doi: 10.1111/cas.14731. Epub 2020 Dec 7.
Testis-specific protein Y-encoded 1 (TSPY1), a Y chromosome-linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl-histone H4 and trimethylated histone H3-lysine 4, two post-translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1-CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen-AR axis-regulated oncogene, suggesting a novel and potential target for PCa therapy.
睾丸特异性蛋白 Y 编码 1（TSPY1）是一种与 Y 染色体相关的癌基因，在前列腺癌（PCa）中经常被激活，其表达与 PCa 的预后不良相关。然而，TSPY1 在 PCa 中的异位转录的原因仍不清楚。在这里，我们观察到 TSPY1 启动子的 CpG 岛（CGI）的甲基化状态与其在不同人类样本中的表达水平呈负相关。组蛋白的两种翻译后修饰，乙酰化组蛋白 H4 和三甲基化组蛋白 H3-赖氨酸 4，占据 TSPY1 启动子，促进了 PCa 细胞中的 TSPY1 表达。此外，我们发现雄激素在 TSPY1-CGI 低甲基化的条件下加速 TSPY1 转录，并促进 PCa 细胞增殖。此外，在 PCa 细胞中检测到雄激素受体（AR）与 TSPY1 启动子的结合，增强了 TSPY1 转录。总之，我们的研究结果确定了 DNA 甲基化作为主要机制，对 PCa 中 TSPY1 表达的调节作用，并揭示了 TSPY1 是雄激素-AR 轴调节的癌基因，为 PCa 治疗提供了一个新的潜在靶点。
