MZF1/SETD1A-FoxM1正反馈环路促进结直肠癌侵袭转移的机制研究

Metastasis is the major cause of death in patients with colorectal cancer (CRC), therefore further characterization of the molecular mechanism underlying CRC metastasis may identify novel therapeutic targets. Previous studies have demonstrated that MZF1 is one of the most important transcription factors regulating progression of CRC. We have also found that elevated expression of MZF1 in CRC tissues correlates with cancer metastasis, however the underlying mechanism is unclear. Bioinformatics analysis of MZF1-associated ChIP-Sequencing and RNA- Sequencing data suggest that MZF1 may bind to the promoter of FoxM1 and regulate its transcription. Moreover, mass spectrometry, immunoprecipitation and whole genome SETD1A ChIP-Sequencing results indicates that MZF1 may recruit a histone methytransferase SETD1A to promote the expression of FoxM1, a potent driver of CRC metastasis. Furthermore, the transcription factor FoxM1 could form a feedback loop to stimulate the expression of both MZF1 and SETD1A in CRC. In light of this evidence, we propose that the novel positive feedback loop of transcriptional complex MZF1/SETD1A and FoxM1 may be crucial for invasion and metastasis of CRC. We will study the molecular mechanisms by which MZF1-SETD1A transcriptional complex act on FoxM1 to stimulate its expression and how FoxM1 regulate MZF1 and SETD1A in CRC cells by multiple molecular and cellular techniques and mouse models of tumor cell metastasis. Together, these findings may identify promising molecular targets to inhibit deadly dissemination of CRC cells in patients.

肿瘤转移是结直肠癌致死主要死因，研究其调控机制具有重要的临床意义。MZF1是调控结直肠癌发生发展的重要转录因子，前期发现MZF1促进结直肠癌侵袭转移，但下游分子机制尚不清楚。ChIP-Seq和RNA测序等实验表明MZF1可结合结直肠癌侵袭转移重要驱动因子FoxM1基因的启动子并激活其表达；质谱与免疫共沉淀、ChIP-Seq等实验表明MZF1与组蛋白甲基化酶SETD1A形成蛋白复合体，可能共同调控FoxM1表达。此外，Western和双荧光素酶报告基因实验表明FoxM1可反馈激活MZF1和SETD1A转录，因此提出科学假说：转录复合体MZF1/SETD1A与转录因子FoxM1形成正反馈环路，促进结直肠癌细胞的侵袭转移。拟采用多种生物学技术和体内侵袭转移模型，研究新的转录复合体MZF1/SETD1A与FoxM1形成正反馈环路促进结直肠癌侵袭转移的分子机制，为抑制结直肠癌转移提供新的干预靶点。

结肠癌恶性增殖的调控机制一直是研究热点。本项目通过生物信息学分析、分子生物学实验、体外实验、体内实验、高通量测序等手段，筛选出结肠癌重要转录因子MZF1，明确了MZF1通过与组蛋白甲基转移酶PRMT1形成转录复合物共同调控下游靶基因SKIL促进结肠癌细胞增殖的调控机制。本项目从转录水平、表观遗传学修饰水平及基因调控水平揭示结肠癌恶性进展，为结肠癌细胞恶性增殖提供了新的靶点。在本项目资助下共计发表SCI论文11篇，其中影响因子5.0以上7篇；培养硕士研究生6名，博士研究生4名。