HOXC10/HDAC介导的p21转录抑制对胃癌细胞周期和增殖的作用及机制

Homeobox (HOX) gene family encodes proteins which function as transcriptional factors and is associated with embryo development and tumorigenesis. Our group have previously screened and verified that the expression of HOXC10 was remarkably upregulated in gastric cancer (GC), and was significantly related to poor prognosis of patients. HOXC10 markedly affected the G1 cell cycle and some crucial cell cycle-related proteins, leading to the proliferation of GC cells and tumor formation in nude mice in vitro and in vivo. Furthermore, the HOXC10 was observed to bind to the promoter of p21 and induce the decreased activity of p21 transcription. Histone deacetylase (HDAC) inhibitor TSA treatment was able to alleviate the repression of p21 transcriptional activity by HOXC10. In clinical sample, animal model and cell molecular studying, this study try to explore role of HOXC10/HDAC induced p21 transcriptional repression in cell cycle-related signal pathway and GC cell proliferation, as well as its clinical value. We will clarify the transcriptional repression of p21 by HOXC10 and analyze the specific binding sites in p21 promoter. We will screen the components of the HOXC10 transcription co-repressors and determine how HOXC10 influence the histone deacetylation and transcriptional activity of p21 by interacting with specific HDAC. The study will reveal the novel molecular mechanism of GC-related gene HOXC10 and is expected to provide potential molecular targets for the diagnosis and treatment of GC.

HOX基因家族编码的蛋白是重要的转录因子，参与胚胎发育和肿瘤发生。前期筛选发现HOXC10在胃癌组织中显著高表达，且其高表达与患者临床预后差相关。HOXC10可调控G1细胞周期和关键周期蛋白，促进胃癌细胞增殖和裸鼠移植瘤形成；HOXC10与p21启动子区结合并抑制其转录活性，负调控p21表达；组蛋白去乙酰化酶（HDAC）抑制剂TSA可逆转HOXC10对p21的转录抑制作用。本研究将在临床、动物和细胞分子水平探讨HOXC10/HDAC-p21转录抑制新机制在胃癌细胞周期信号通路及细胞增殖行为中的作用及临床价值；明确HOXC10对p21的转录抑制作用，分析HOXC10与p21启动子的具体结合位点；筛选HOXC10转录共抑制子，阐明HOXC10与何种HDAC协同分子互作，影响p21组蛋白乙酰化水平和转录活性。项目将揭示胃癌相关基因HOXC10新的分子作用机理，为胃癌发生发展提供潜在分子诊治靶点。

HOXC10是HOX基因家族编码蛋白，是一种转录因子，参与胚胎发育和肿瘤发生，其在胃癌中的作用调控机制尚未阐明。我们前期发现HOXC10在胃癌组织中显著高表达，促进胃癌细胞增殖和裸鼠移植瘤形成；过表达HOXC10胃癌细胞周期G1-S期转换明显加快，而干扰HOXC10细胞周期阻滞在G1期。本研究将在临床、动物和细胞分子水平探讨HOXC10在胃癌细胞周期及细胞增殖调控中的作用及具体分子机制。我们研究发现HOXC10的高表达是胃癌预后差的一个独立预测因素。运用ChIP-seq技术结合信息学分析筛选验证，发现CCND1（cyclin D1）是HOXC10下游关键靶基因。HOXC10可以直接结合在CCND1的启动子区，在转录水平影响CCND1的表达。HOXC10稳定敲减后的胃癌细胞周期表现出明显的G1/S期阻滞，而过表达CCND1质粒可明显缓解HOXC10敲减对胃癌细胞周期G1/S期阻滞的影响。CCND1和HOXC10的表达在组织上存在正相关，生存时间分析发现CCND1和HOXC10高表达的胃癌患者均表现为较差的预后。本研究通过揭示胃癌相关基因HOXC10新的分子作用机理，为胃癌发生发展提供潜在分子诊治靶点。