启动子G-四链体调控癌基因hnRNP K及其通过i-motif影响下游c-myc转录表达的分子机制研究

hnRNP K蛋白在许多癌细胞中都过表达，是潜在抗癌药物靶标。它还是细胞核中的重要转录调节蛋白，可与癌基因c-myc启动子区域的富C序列/i-motif结合，上调c-myc的转录表达。我们通过生物信息学和体内外实验发现,该蛋白的基因启动子区域存在富G序列，在形成稳定G-四链体后，显著下调hnRNP K转录表达。本项目将在此重要发现基础上，深入研究hnRNP K基因启动子G-四链体对该基因的转录表达调控机制；进一步探讨hnRNP K蛋白通过c-myc基因启动子富C序列/i-motif调控c-myc转录表达的机制；合成筛选hnRNP K及其基因启动子G-四链体和c-myc启动子i-motif的选择性配体，为上述分子机制研究提供有力工具。本项目将为阐明hnRNP K的转录调控网络和i-motif在c-myc转录调控中的作用和意义，也为新型抗癌药物的研究提供依据。

hnRNP K is an important protein overexpressed in many cancer cells, and therefore, is a potential antitumor drug target. It is an important transcriptional regulation protein present in the nucleus, which can up-regulate the transcription and expression of c-myc, through its binding with C-rich sequence/i-motif on c-myc gene promoter region. In our recent bioinformatic and in vivo and in vitro studies, we found a G-rich sequence on the upstream promoter of hnRNP K gene, which could form stable G-quadruplex, and down-regulate transcription and overexpression level of hnRNP K. Based on this important finding, we plan to carry out in-depth mechanistic studies for transcriptional regulation of hnRNP K gene by this G-quadruplex. We also plan to study the mechanism for hnRNP K protein to regulate c-myc gene transcription through its binding with c-myc promoter C-rich sequence/i-motif. We will also synthesize and screen selective binding ligands for protein hnRNP K and its gene promoter G-quadruplex as well as c-myc promoter i-motif as probes, providing powerful tools for the above mechanistic studies. This project will provide a new theoretical basis for elucidating transcriptional regulatory network of hnRNP K, and function and significance of i-motif in regulating c-myc gene transcription and expression, as well as discovery of new types of anti-cancer drugs.