天然来源小分子grifolin干预肿瘤转移表观遗传机制研究

We screened the extracts from Albatrellus confluens bodies of Higher Fungi and acquired grifolin,a novel compound.It was found that grifolin not only had certain selectivity to cancerous and non-cancerous cell lines, but also significantly decreased kinase activity of ERK1/2 in MAPK pathway in vitro and in vivo.We will further investigate the anti-invasion and metastasis mechanism of grifolin through activating the metastatic suppressor genes. On one hand, by intervening with ERK1/2 kinase activity,it regulates the downstream Elk1-DNMT1 pathway to suppress the transcription of dnmt1 gene,thereby demethylation of the promoters of metastatic suppressor genes. On the other hand, by activating transcription factor p53, grifolin inhibits the function of SIRT1/2 to increase the acylation level of H3 and H4 at TSS region of metastatic suppressor genes. The research will provide novel target and drug action mechanism for anti-tumor metastasis and present new evidence for grifolin to act as an anti-tumor metastasis natural candidate compound.

我们从高等真菌地花菌属 (Albatrellus confluens)子实体提取物中筛选出了具有抗肿瘤活性的新型小分子grifolin，并发现其不但对肿瘤细胞系和非肿瘤细胞系具有一定的选择性，而且能显著降低MAPK信号通路中ERK1/2激酶的体内外激酶活性。本项目从表观遗传调控的角度，进一步探讨天然来源小分子grifolin通过干扰ERK1/2激酶活性，调节下游Elk1-DNMT1通路，抑制dnmt1基因的转录，使与侵袭转移相关基因启动子区发生去甲基化；另一方面，通过活化转录因子p53，抑制组蛋白去乙酰化酶SIRT1/2功能，使肿瘤转移抑制基因的转录起始区域组蛋白H3和H4乙酰化水平增加；最终使这些基因重新活化表达，发挥抗肿瘤侵袭转移功能的分子机制。这将为抗肿瘤转移研究提供新的靶点和药物作用机理；同时也为grifolin作为抗肿瘤转移的候选天然小分子化合物提供新的理论依据。

我们从高等真菌地花菌属 (Albatrellus confluens)子实体提取物中筛选出了具有抗肿瘤活性的新型小分子grifolin，并发现其不但对肿瘤细胞系和非肿瘤细胞系具有一定的选择性，而且能显著降低MAPK信号通路中ERK1/2激酶的体内外激酶活性。本项目从表观遗传调控的角度，进一步明确天然来源小分子grifolin通过干扰ERK1/2激酶活性，调节下游Elk1-DNMT1通路，抑制甲基化转移酶dnmt1基因的转录；另一方面，通过活化转录因子p53，抑制组蛋白去乙酰化酶SIRT1功能。两种机制协同作用，使侵袭转移抑制基因重新活化表达，发挥抗肿瘤功能的分子机制。这将为抗肿瘤转移研究提供新的靶点和药物作用机理；同时也为grifolin作为抗肿瘤转移的候选天然小分子化合物提供新的理论依据。