UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells

UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is an important epigenetic regulator that plays a part in DNA methylation, protein methylation and ubiquitination. It is also frequently overexpressed in many types of cancers, including cervical cancer, which is caused by human papillomavirus (HPV). In this study, we showed that UHRF1 was up-regulated in HPV oncogene E7 expressing cells and HPV-positive cervical cancer cells. We demonstrated that UHRF1 down-regulated the expression of UBE2L6 gene that encodes the ISG15-conjugating enzyme UbcH8. Overexpression of UHRF1 reduced UBE2L6 while knockdown UHRF1 elevated the expression of UBE2L6. We showed that UHRF1 regulated UBE2L6 gene by promoter hypermethylation in cervical cancer cells. Consistent with the functions of UHRF1, restored expression of UbcH8 induced apoptosis. These findings establish UBE2L6 as a novel target of UHRF1 that regulates the apoptosis function of UHRF1. Our studies suggest that UHRF1/ UbcH8 can be manipulated for therapy in cervical cancer.

UHRF1（ubiquitin-like, containing PHD and RING finger domains 1，泛素样含PHD和RING指结构域蛋白1）是一类重要的表观遗传调控因子，参与DNA甲基化、蛋白质甲基化及泛素化调控过程。该因子在多种癌症中常出现过表达现象，其中包括由人乳头瘤病毒（human papillomavirus, HPV）感染引发的宫颈癌。本研究发现，在表达HPV癌基因E7的细胞以及HPV阳性宫颈癌细胞中，UHRF1的表达水平显著上调。我们证实，UHRF1可下调编码ISG15偶联酶UbcH8的UBE2L6基因的表达。过表达UHRF1会降低UBE2L6的表达水平，而敲低UHRF1则可上调UBE2L6的转录表达。研究表明，在宫颈癌细胞中，UHRF1通过启动子高甲基化调控UBE2L6基因的表达。与UHRF1的功能特性一致，恢复UbcH8的表达可诱导细胞凋亡。上述研究结果证实UBE2L6是UHRF1的全新靶标，且UBE2L6参与调控UHRF1介导的细胞凋亡功能。本研究提示，可通过靶向调控UHRF1/UbcH8通路以开展宫颈癌的靶向治疗。