Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan.
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Oncogene. 2014 Jun 5;33(23):2978-86. doi: 10.1038/onc.2013.262. Epub 2013 Jul 29.
Sgf29, a component of the SPT-ADA-GCN5 acetyltransferase (SAGA) complex, binds H3K4me2/3 marks and leads to histone H3 acetylation. Previously, we found that downregulation of Sgf29 suppresses c-Myc-mediated malignant transformation. Nonetheless, the upstream regulator of the Sgf29 gene is not yet known. Here, we report that Sry (sex-determining region Y), an HMG (high-mobility group) domain containing transcription factor, directly upregulates Sgf29 gene expression. Sry expression was deregulated in two out of the four tested male rodent hepatocellular carcinoma (rHCC) cell lines. Luciferase reporter and chromatin immunoprecipitation assays indicated that Sry could bind HMG-boxes in the proximal promoter region of the Sgf29 gene. Knockdown of Sry robustly lowered anchorage-independent growth, invasiveness and tumorigenicity of rHCC cells, whereas ectopic expression of Sry conferred more malignant properties. Thus, these data show that Sry is involved in male-specific malignant conversion of rHCCs via Sgf29 upregulation.
Sgf29 是 SPT-ADA-GCN5 乙酰转移酶（SAGA）复合物的一个组成部分，它结合 H3K4me2/3 标记，并导致组蛋白 H3 乙酰化。先前，我们发现 Sgf29 的下调抑制了 c-Myc 介导的恶性转化。然而，Sgf29 基因的上游调节因子尚不清楚。在这里，我们报告说 Sry（性别决定区 Y），一种含有 HMG（高迁移率族）结构域的转录因子，直接上调 Sgf29 基因的表达。在测试的四个雄性啮齿动物肝癌 (rHCC) 细胞系中的两个中，Sry 的表达被失调。荧光素酶报告基因和染色质免疫沉淀分析表明，Sry 可以结合 Sgf29 基因近端启动子区域的 HMG 盒。Sry 的敲低显著降低了 rHCC 细胞的锚定非依赖性生长、侵袭性和致瘤性，而 Sry 的异位表达赋予了更恶性的特性。因此，这些数据表明，Sry 通过上调 Sgf29 参与了雄性特异性 rHCC 的恶性转化。
