组蛋白去甲基化酶JMJD2D在结直肠癌发生发展中的作用及其分子机制

Histone demethylase JMJD2D can demethylate histone 3 lysine 9 (H3K9) to promote gene expression, its role in colorectal cancer (CRC) progression remains unclear. Our prelimilary resuts showed that JMJD2D was upregulated in several human CRC samples and CRC cell lines, and downregulation of JMJD2D could inhibit the proliferation of CRC cells. Furthermore, JMJD2D could interact with β-catenin to enhance the tansactivation activity of β-catenin, which plays an important role in CRC progression. Accordingly, we propose that JMJD2D can serve as a transcriptional coactivator to cooperate with Wnt/β-catenin signaling to promote CRC progression. To test this hypothesis, we will first study the effect of downregulation of JMJD2D on the proliferation, tumorigenesis, invasiveness and metastasis of CRC cells as well as the molecular mechanism by which JMJD2D enhances the tansactivation activity of β-catenin; secondly, we will use JMJD2D knockout mice to study the effect of SRC-3 deficiency on the progression of CRC; lastly, we will measure the correlation of JMJD2D expression and the progression of CRC as well as the expression of Wnt/β-catenin target genes in human CRC samples to reveal the role and mechanism of JMJD2D in CRC progression.

组蛋白去甲基化酶JMJD2D能使组蛋白H3K9去甲基化而促进基因表达, 其在结直肠癌发生发展中的作用仍不清楚。我们前期研究发现人结直肠癌样本及结直肠癌细胞存在JMJD2D过表达;下调JMJD2D表达能抑制结直肠癌细胞增殖; JMJD2D能与β-catenin相互作用而增强其转录活性。这些结果表明JMJD2D可能作为转录辅激活子通过增强Wnt/β-catenin信号通路促进结直肠癌发生发展。为了验证这一假说，我们首先下调JMJD2D的表达，研究其对结直肠癌细胞增殖、成瘤、侵袭和转移的影响及机制；接着研究JMJD2D增强Wnt/β-catenin信号通路的分子机制；再用JMJD2D敲除小鼠研究JMJD2D缺失对结直肠癌发生发展的影响；最后检测人结直肠癌组织样本中JMJD2D表达与结直肠癌发展以及Wnt/β-catenin靶基因表达的相关性，揭示JMJD2D在结直肠癌发生发展中的作用及分子机制。

组蛋白去甲基化酶JMJD2D能使组蛋白H3K9去甲基化而促进基因表达, 其在结直肠癌发生发展中的作用仍不清楚。我们前期研究发现人结直肠癌样本及结直肠癌细胞存在JMJD2D过表达;下调JMJD2D表达能抑制结直肠癌细胞增殖;JMJD2D能与β-catenin相互作用而增强其转录活性。这些结果表明JMJD2D可能作为转录辅激活子通过增强Wnt/β-catenin信号通路促进结直肠癌发生发展。在本研究中我们首先下调JMJD2D的表达，发现其降低结直肠癌细胞增殖、成瘤、侵袭和转移；发现JMJD2D是通过辅激活β-catenin、Hedgehog和HIF1信号通路来促进结直肠癌发生和发展；发现敲除JMJD2D可显著减少AOM/DSS 所诱导的结直肠癌进程；发现人结直肠癌组织样本中JMJD2D表达与结直肠癌发展以及Wnt/β-catenin靶基因表达具有正相关性；本研究揭示JMJD2D促进结直肠癌发生发展中的重要作用及分子机制，为结直肠癌的治疗提供新思路。