From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China.
J Biol Chem. 2018 Jul 6;293(27):10606-10619. doi: 10.1074/jbc.RA118.001730. Epub 2018 May 25.
The histone demethylase Jumonji domain containing 1A (JMJD1A) is overexpressed in multiple tumors and promotes cancer progression. JMJD1A has been shown to promote colorectal cancer (CRC) progression, but its molecular role in CRC is unclear. Here, we report that JMJD1A is overexpressed in CRC specimens and that its expression is positively correlated with that of proliferating cell nuclear antigen (PCNA). JMJD1A knockdown decreased the expression of proliferative genes such as c-, cyclin D1, and , suppressed CRC cell proliferation, arrested cell cycle progression, and reduced xenograft tumorigenesis. Furthermore, JMJD1A knockdown inhibited CRC cell migration, invasion, and lung metastasis by decreasing matrix metallopeptidase 9 (MMP9) expression and enzymatic activity. Moreover, bioinformatics analysis of GEO profile datasets revealed that JMJD1A expression in human CRC specimens is positively correlated with the expression of Wnt/β-catenin target genes, including c-, cyclin D1, and Mechanistically, JMJD1A enhanced Wnt/β-catenin signaling by promoting β-catenin expression and interacting with β-catenin to enhance its transactivation. JMJD1A removed the methyl groups of H3K9me2 at the promoters of c- and genes. In contrast, the JMJD1A variant, which lacked demethylase activity, did not demethylate H3K9me2 at these promoters, failed to assist β-catenin to induce the expression of Wnt/β-catenin target genes, and failed to promote CRC progression. These findings suggest that JMJD1A's demethylase activity is required for Wnt/β-catenin activation. Of note, high JMJD1A levels in CRC specimens predicted poor cancer outcomes. In summary, JMJD1A promotes CRC progression by enhancing Wnt/β-catenin signaling, implicating JMJD1A as a potential molecular target for CRC management.
组蛋白去甲基化酶 JUMONJI 结构域包含蛋白 1A（JMJD1A）在多种肿瘤中过表达，并促进癌症进展。已经表明 JMJD1A 促进结直肠癌（CRC）的进展，但它在 CRC 中的分子作用尚不清楚。在这里，我们报告 JMJD1A 在 CRC 标本中过表达，并且其表达与增殖细胞核抗原（PCNA）的表达呈正相关。JMJD1A 敲低降低了增殖基因如 c-、cyclin D1 和 的表达，抑制 CRC 细胞增殖，阻滞细胞周期进程，并减少异种移植肿瘤发生。此外，JMJD1A 敲低通过降低基质金属蛋白酶 9（MMP9）表达和酶活性抑制 CRC 细胞迁移、侵袭和肺转移。此外，GEO 谱数据集的生物信息学分析表明，人 CRC 标本中 JMJD1A 的表达与 Wnt/β-catenin 靶基因的表达呈正相关，包括 c-、cyclin D1 和 。在机制上，JMJD1A 通过促进β-catenin 表达并与β-catenin 相互作用增强其转录激活来增强 Wnt/β-catenin 信号。JMJD1A 去除了 c-和 基因启动子上 H3K9me2 的甲基基团。相比之下，缺乏去甲基酶活性的 JMJD1A 变体不能在这些启动子上去除 H3K9me2，不能协助 β-catenin 诱导 Wnt/β-catenin 靶基因的表达，也不能促进 CRC 的进展。这些发现表明 JMJD1A 的去甲基酶活性是 Wnt/β-catenin 激活所必需的。值得注意的是，CRC 标本中高 JMJD1A 水平预示着不良的癌症结局。总之，JMJD1A 通过增强 Wnt/β-catenin 信号促进 CRC 进展，提示 JMJD1A 可能成为 CRC 管理的潜在分子靶点。
