A regulatory circuit HP1γ/miR-451a/c-Myc promotes prostate cancer progression

Heterochromatin protein 1 gamma (HP1 gamma) has been implicated in carcinogenesis of various cancer types. However, the role of HP1 gamma in prostate cancer (PCa) progression and the underlying molecular mechanisms remain largely unknown. We found that HP1 gamma is upregulated in PCa and elevated levels of HP1 gamma in PCa predict poor outcome. In addition, depletion of HP1 gamma in PCa cells not only repressed proliferation and induced apoptosis but also impaired tumorigenicity. We also found that c-Myc was capable of upregulating HP1 gamma by directly binding to the E-box element in the first intron of HP1 gamma gene, and the upregulated HP1 gamma, 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 HP1 gamma loss-induced PCa cell apoptosis, whereas miR-451a overexpression repressed cell survival by targeting and downregulating c-Myc. The association among c-Myc, HP1 gamma and miR-451a was further confirmed in human clinical samples. Therefore, we propose that an HP1 gamma/miR-451a/c-Myc regulatory circuitry exists in PCa cells and this circuit has a crucial role in PCa progression.