Li Na, Dhar Shilpa S, Chen Tsai-Yu, Kan Pu-Yeh, Wei Yongkun, Kim Jae-Hwan, Chan Chia-Hsin, Lin Hui-Kuan, Hung Mien-Chie, Lee Min Gyu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
Cancer Res. 2016 Feb 15;76(4):831-43. doi: 10.1158/0008-5472.CAN-15-0906. Epub 2016 Jan 8.
Entire or partial deletions of the male-specific Y chromosome are associated with tumorigenesis, but whether any male-specific genes located on this chromosome play a tumor-suppressive role is unknown. Here, we report that the histone H3 lysine 4 (H3K4) demethylase JARID1D (also called KDM5D and SMCY), a male-specific protein, represses gene expression programs associated with cell invasiveness and suppresses the invasion of prostate cancer cells in vitro and in vivo. We found that JARID1D specifically repressed the invasion-associated genes MMP1, MMP2, MMP3, MMP7, and Slug by demethylating trimethyl H3K4, a gene-activating mark, at their promoters. Our additional results demonstrated that JARID1D levels were highly downregulated in metastatic prostate tumors compared with normal prostate tissues and primary prostate tumors. Furthermore, the JARID1D gene was frequently deleted in metastatic prostate tumors, and low JARID1D levels were associated with poor prognosis in prostate cancer patients. Taken together, these findings provide the first evidence that an epigenetic modifier expressed on the Y chromosome functions as an anti-invasion factor to suppress the progression of prostate cancer. Our results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer.
男性特异性Y染色体的全部或部分缺失与肿瘤发生相关，但位于该染色体上的任何男性特异性基因是否发挥肿瘤抑制作用尚不清楚。在此，我们报告组蛋白H3赖氨酸4（H3K4）去甲基化酶JARID1D（也称为KDM5D和SMCY），一种男性特异性蛋白，可抑制与细胞侵袭相关的基因表达程序，并在体外和体内抑制前列腺癌细胞的侵袭。我们发现JARID1D通过在启动子处将三甲基H3K4（一种基因激活标记）去甲基化，特异性抑制侵袭相关基因MMP1、MMP2、MMP3、MMP7和Slug。我们的其他结果表明，与正常前列腺组织和原发性前列腺肿瘤相比，转移性前列腺肿瘤中JARID1D水平高度下调。此外，JARID1D基因在转移性前列腺肿瘤中经常缺失，JARID1D水平低与前列腺癌患者的不良预后相关。综上所述，这些发现提供了首个证据，即Y染色体上表达的一种表观遗传修饰因子作为一种抗侵袭因子来抑制前列腺癌的进展。我们的结果还突出了将JARID1D用作晚期前列腺癌预后标志物的临床前理论依据。
