Departments of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
J Mol Endocrinol. 2013 Apr 23;50(3):401-9. doi: 10.1530/JME-13-0024. Print 2013 Jun.
Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1α and HP1γ, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1γ, but not HP1α, reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1α and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1γ had no effect. Similarly, HP1α overexpression promoted 22Rv1 cell growth, whereas HP1γ knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer.
雄激素受体（AR）信号通路对于前列腺癌的发生发展以及去势抵抗性前列腺癌的进展至关重要。我们之前的研究表明，异染色质蛋白 1（HP1）β亚型作为 AR 共激活因子在 AR 信号通路的转激活中发挥关键作用，促进前列腺癌细胞增殖。然而，其他 HP1 亚型（HP1α 和 HP1γ）在 AR 表达和前列腺癌中的作用尚不清楚。在这里，我们发现敲低 HP1γ而非 HP1α通过诱导 LNCaP 细胞 G1 期细胞周期停滞来降低 AR 表达和细胞增殖。相反，全长 HP1α及其 C 端缺失突变体的过表达增加了 AR 表达和细胞生长，而 HP1γ 的过表达则没有影响。同样，HP1α 的过表达促进了 22Rv1 细胞的生长，而 HP1γ 的敲低则降低了 CxR 细胞（LNCaP 的去势抵抗性衍生物）的增殖。综上所述，HP1 亚型在前列腺癌中明显增强了 AR 信号通路和细胞生长。因此，沉默 HP1β 和 HP1γ 可能是治疗前列腺癌的一种有前途的治疗策略。
