Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA.
Program in Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA.
J Biol Chem. 2020 Jun 19;295(25):8537-8549. doi: 10.1074/jbc.RA119.010080. Epub 2020 May 5.
Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth.
中心体蛋白在许多人类恶性肿瘤中都有过表达，但其对疾病进展的功能和机制贡献尚未得到阐明。着丝粒组蛋白 H3 变体着丝粒蛋白 A（CENPA）是一种决定着丝粒身份的表观遗传标记。在这里，我们使用一系列方法，包括 RNA 测序和 ChIP 测序分析、基于免疫组织化学的组织微阵列和各种细胞生物学测定，证明 CENPA 在前列腺癌组织和细胞系中高度过表达，并且 CENPA 的表达水平与患者的疾病阶段相关。功能获得和功能丧失实验证实 CENPA 促进了前列腺癌细胞系的生长。整合测序实验的结果表明 CENPA 作为转录调节剂的一个先前未被识别的功能，调节关键增殖、细胞周期和着丝粒/动粒基因的表达。综上所述，我们的研究结果表明 CENPA 过表达对前列腺癌的生长至关重要。
