State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
Collaborative Innovation Center of Genetics and Development, Shanghai, China.
Oncogene. 2018 Jan 25;37(4):415-426. doi: 10.1038/onc.2017.332. Epub 2017 Oct 2.
Heterochromatin protein 1γ (HP1γ) has been implicated in carcinogenesis of various cancer types. However, the role of HP1γ in prostate cancer (PCa) progression and the underlying molecular mechanisms remain largely unknown. We found that HP1γ is upregulated in PCa and elevated levels of HP1γ in PCa predict poor outcome. In addition, depletion of HP1γ in PCa cells not only repressed proliferation and induced apoptosis but also impaired tumorigenicity. We also found that c-Myc was capable of upregulating HP1γ by directly binding to the E-box element in the first intron of HP1γ gene, and the upregulated HP1γ, in turn, repressed the expression of miR-451a by enhancing H3K9 methylation at the promoter region of miR-451a. Furthermore, reduction of miR-451a significantly reversed HP1γ loss-induced PCa cell apoptosis, whereas miR-451a overexpression repressed cell survival by targeting and downregulating c-Myc. The association among c-Myc, HP1γ and miR-451a was further confirmed in human clinical samples. Therefore, we propose that an HP1γ/miR-451a/c-Myc regulatory circuitry exists in PCa cells and this circuit has a crucial role in PCa progression.
异染色质蛋白 1γ（HP1γ）参与了多种癌症类型的致癌作用。然而，HP1γ 在前列腺癌（PCa）进展中的作用及其潜在的分子机制在很大程度上仍不清楚。我们发现 HP1γ 在 PCa 中上调，并且 PCa 中 HP1γ 的高水平预示着不良预后。此外，在 PCa 细胞中耗尽 HP1γ 不仅抑制增殖并诱导细胞凋亡，而且还损害致瘤性。我们还发现 c-Myc 能够通过直接结合 HP1γ 基因第一内含子中的 E 盒元件而上调 HP1γ，而上调的 HP1γ 反过来通过增强 miR-451a 启动子区域的 H3K9 甲基化来抑制 miR-451a 的表达。此外，降低 miR-451a 可显著逆转 HP1γ 缺失诱导的 PCa 细胞凋亡，而 miR-451a 过表达通过靶向和下调 c-Myc 来抑制细胞存活。c-Myc、HP1γ 和 miR-451a 之间的关联在人类临床样本中得到了进一步证实。因此，我们提出 HP1γ/miR-451a/c-Myc 调控回路存在于 PCa 细胞中，该回路在 PCa 进展中起着关键作用。
