PHF6在结直肠癌转移中的作用及机制

Colorectal cancer (CRC) is a major cause of mortality in western society with a 5-year survival rate of approximately 50%. In China, the incidence of colorectal cancer has been rising significantly. The morbidity and mortality rank the third and fifth, respectively. Metastasis to the liver and lungs is the primary cause of death, which occurs in up to 25% of patients at present. Epithelial-mesenchymal transition (EMT) is known as the initial step of tumor metastasis. Although it has been reported that PHF6 interacts with NURD and PAF1 complexes, little is known about its other interaction proteins, gene targets and biological functions. Our preliminary studies have shown PHF6 interacted with PRC2 complex; PHF6 is increased in colorectal cancer and the inhibition of PHF6 reduced invasiveness of colorectal cancer cells, indicating PHF6, as a transcription repressor, may play a role in the metastasis of colorectal cancer cells. This project intends to determine the interaction between PHF6 and PRC2 complexes using affinity chromatography, mass spectrometry, immunoprecipitation and FPLC; identify genes that are regulated by PHF6 and PRC2 complex using ChIP-Seq technology. This project further intends to explore the biological function of PHF6 in metastasis in colorectal cancer cells and the underlying molecular mechanisms. This study will provide better understanding of the roles of PHD zinc finger protein family in transcriptional regulation and chromatin modification related to metastasis in colorectal cancer, which may further offer a potential new target for the diagnosis, treatment and prognosis of colorectal cancer.

结直肠癌是严重威胁人类健康的主要恶性肿瘤之一，全球发病率和死亡率分别位于第三位和第四位。肿瘤转移是导致结直肠癌患者死亡的主要原因。上皮-间质转换（EMT）是肿瘤转移的起始步骤。尽管已有报道PHF6与NURD、PAF1复合体有相互作用，但其在转录调控和组蛋白修饰中的作用和机制、其调控靶基因和在结直肠癌转移中的作用未见报道。我们前期研究发现PHF6和PRC2复合体相互作用，PHF6在结直肠癌中高表达，其下调抑制结直肠癌细胞的侵袭。本课题利用蛋白质亲和层析联合质谱和免疫共沉淀等技术分析PHF6的相互作用蛋白和利用ChIP-Seq技术探求PHF6和PRC2复合体共同调控的靶基因为突破点，深入探讨PHF6参与转录调控和组蛋白修饰的新机理，探讨PHF6在结直肠癌细胞转移中的作用及分子机制，为进一步认识PHD锌指蛋白在基因转录调控和组蛋白修饰及在结肠癌转移中的作用奠定基础，为结直肠癌治疗和诊断提供线索。