Department of Cancer Biology and Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Cancer Res. 2011 Feb 1;71(3):964-75. doi: 10.1158/0008-5472.CAN-10-3172. Epub 2010 Dec 28.
The Sirtuin family of proteins (SIRT) encode a group of evolutionarily conserved, NAD-dependent histone deacetylases, involved in many biological pathways. SIRT1, the human homologue of the yeast Silent Information Regulator 2 (Sir2) gene, deacetylates histones, p300, p53, and the androgen receptor. Autophagy is required for the degradation of damaged organelles and long-lived proteins, as well as for the development of glands such as the breast and prostate. Herein, homozygous deletion of the Sirt1 gene in mice resulted in prostatic intraepithelial neoplasia (PIN) associated with reduced autophagy. Genome-wide gene expression analysis of Sirt1(-/-) prostates demonstrated that endogenous Sirt1 repressed androgen responsive gene expression and induced autophagy in the prostate. Sirt1 induction of autophagy occurred at the level of autophagosome maturation and completion in cultured prostate cancer cells. These studies provide novel evidence for a checkpoint function of Sirt1 in the development of PIN and further highlight a role for SIRT1 as a tumor suppressor in the prostate.
Sirtuin 家族蛋白（SIRT）编码一组进化上保守的、依赖 NAD 的组蛋白去乙酰化酶，参与许多生物学途径。SIRT1 是酵母沉默信息调节因子 2（Sir2）基因的人类同源物，可使组蛋白、p300、p53 和雄激素受体去乙酰化。自噬是降解受损细胞器和长寿蛋白所必需的，也是乳房和前列腺等腺体发育所必需的。本文中，小鼠 Sirt1 基因的纯合缺失导致与自噬减少相关的前列腺上皮内瘤形成（PIN）。Sirt1（-/-）前列腺的全基因组基因表达分析表明，内源性 Sirt1 抑制雄激素反应基因的表达，并在前列腺中诱导自噬。Sirt1 在培养的前列腺癌细胞中诱导自噬发生在自噬体成熟和完成的水平上。这些研究为 Sirt1 在 PIN 发展中的检查点功能提供了新的证据，并进一步强调了 SIRT1 在前列腺中作为肿瘤抑制因子的作用。
