宫颈癌是最常见的三大妇科肿瘤之一，且绝大多数都源于某种特定类型的高危型人乳头瘤病毒(HPV)的持续感染，肿瘤细胞表现出高水平的蛋白糖基化特征，但介导其糖基化改变的分子机制目前还不清楚。申请人前期的研究发现组蛋白甲基化修饰酶KDM5C在高危HPV致癌细胞中被降解并由此激活了致癌基因超级增强子，还发现KDM5C可显著抑制与YAP1超级增强子相关的lncRNA YAP1-AS的转录。由于YAP1参与调控肿瘤细胞蛋白糖基化，且在宫颈癌细胞系中敲除KDM5C可导致蛋白糖基化水平升高。由此推测：抑癌因子KDM5C在宫颈癌细胞中缺失促使YAP1-AS转录水平升高，并顺式上调YAP1的表达，进而促进宫颈癌细胞蛋白糖基化和肿瘤的增殖与侵袭能力。因此，本项目拟在前期研究基础上，揭示KDM5C通过YAP1-AS介导的肿瘤表观遗传和蛋白糖基化之间的调控机制，为高危HPV阳性宫颈癌患者的“个体化”治疗提供新的思路。

Cervical cancer is one of the three most common gynecological tumors, and most of them are caused by the persistent infection of a certain type of high-risk human papillomavirus (HPV). Tumor cells show high levels of protein glycosylation characteristics, but the mechanism of mediating glycosylation change is still unclear. The proposer’s previous studies found that the histone methylation modification enzyme KDM5C was degraded in high-risk HPV carcinogenic cells and thus activated the super enhancers. Combining with the ChIP-seq and transcriptome analyses, further studies found that KDM5C significantly regulated the transcription of YAP1-AS, a long non-coding RNA related to the YAP1 super enhancer. Because YAP1 is involved in regulation of tumor cell protein glycosylation, and knocking out KDM5C in cervical cancer cell lines resulted in higher levels of protein glycosylation, it is speculated that the absence of the tumor suppressor KDM5C in cervical cancer cells promotes the transcription of YAP1-AS, and the expression of YAP1 is up-regulated in cis, which in turn promotes the glycosylation of cervical cancer cell proteins and the ability of tumor proliferation and invasion. On the basis of previous studies, this proposal aims to reveal the regulation mechanism between tumor epigenetic and glycosylation mediated by KDM5C through YAP1-AS, so as to provide a new idea for the "individualized" treatment of high-risk HPV positive cervical cancer patients.