KDM4A-Sox9转录复合体激活AXL表达促进结肠癌转移的分子机制

Aberrancies in histone methylation modification is key feature of tumorigenesis and malignant progression, but it remains unclear whether and how the histone demethylase KDM4A contributes to colon cancer metastasis. We have found that KDM4A expression is elevated in colon cancer tissues and high levels of KDM4A expression correlates with cancer progression and reduced patient survival. Moreover, Depleting KDM4A suppresses motility and invasion of colon cancer cells in vitro. Bioinformatics analysis of whole genome KDM4A Chip-sequencing results and KDM4A-associated gene expression profiles suggest that KDM4A may bind to the promoter of AXL and regulate its transcription. Indeed, our preliminary experiment results show that knockdown of KDM4A down-regulates the expression of AXL in colon cancer cells. Furthermore, we have identified that the transcription factor Sox9 may potentially regulate the expression of AXL and that Sox9 interacts with KDM4A in colon cancer cells, suggesting that the KDM4A-Sox9 protein complex may be recruited to the AXL gene loci to synergistically regulate AXL expression. Since previous studies have demonstrated a critical role of AXL in promoting tumor invasion and metastasis, in this proposal we will further study the molecular mechanisms by which the novel KDM4A-Sox9 protein complex might activate AXL expression in a cooperative manner to drive invasion and metastasis of colon cancer. Together, these anticipated findings may identify promising molecular targets to combat the dissemination of colon cancer cells and potentially improve clinical therapeutic outcomes.

肿瘤发生演进常伴随异常的组蛋白甲基化修饰，但组蛋白去甲基化酶KDM4A促进结肠癌转移的分子机制不详。我们前期发现结肠癌高表达KDM4A，促进肿瘤细胞运动侵袭，与肿瘤进展密切相关；生物信息学分析KDM4A相关Chip-Seq和基因表达谱，以及我们的预实验表明，KDM4A与AXL启动子结合且上调结肠癌细胞AXL表达。我们进一步研究发现Sox9可能是调控AXL表达的转录因子之一，免疫共沉淀实验表明KDM4A与Sox9形成蛋白复合体，可能结合AXL基因启动子。由于AXL高表达促进多种肿瘤的侵袭转移，我们提出假说：“KDM4A协同Sox9转录激活AXL表达，可能是结肠癌侵袭转移的机制之一”，探讨一个新的KDM4A-Sox9蛋白复合体通过表观修饰和转录激活的协同机制，调控AXL表达的分子基础，以及KDM4A-Sox9轴在结肠癌转移中的作用，为抑制结肠癌侵袭转移提供新的分子靶点和实验依据。

肿瘤发生常伴随异常的组蛋白甲基化修饰，但组蛋白去甲基化酶促进结肠癌转移的分子机制不详。目通过分子生物学、细胞水平、动物水平等实验，我们发现KDM4A与Sox9形成蛋白复合体，及对肿瘤细胞系侵袭及迁移的功能的影响。另外，我们也发现另外一个组蛋白去甲基化酶LSD1可能协同转录因子STAT3通过转录因子翻译后修饰和组蛋白甲基化修饰调控下游癌基因表达，进而促进结肠癌增殖；我们还在项目资助下研究了完成MZF1过表达和干扰慢病毒载体的构建；在结肠癌细胞株中验证MZF1对结肠癌体内体外增殖的调控作用；精氨酸特异性组蛋白甲基化酶 PRMT1在结直肠癌中的表达，发现其与结直肠癌细胞增殖密切相关，是一个临床预后相关指标。本项目资助获得的研究成果已发表SCI论文6篇，其中影响因子5.0以上4篇；培养硕士研究生3名，博士研究生1名。