Cpg Binding Protein Promotes Cell Proliferation Through H3k4 Methylation In Ovarian Cancer

E3 ubiquitin ligase CRL4 complex activation requires cullin neddylation. MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, reportedly blocked cullin neddylation and inactivated cullin (CUL)-RING E3 ligases (CRLs). Studies have shown that MLN4924 inhibits cell proliferation and survival. We examined the oncostatic and cytotoxic properties of MLN4924 in ovarian cancer. MLN4924 blocked human cancer cell proliferation in nude mice by inhibiting CpG binding protein CFP1 expression. Loss of CFP1 reduced cell growth, promoted apoptosis, and increased senescence. CFP1-dependent H3K4 trimethylation is necessary to maintain the expression of target genes in ovarian cancer cells. We identified bone marrow stromal cell antigen 2 (BST2) and noggin (NOG) as direct targets of CFP1. Their expression was selectively induced by CFP1 deletion. Furthermore, deletion of NOG and overexpression of BST2 prevented the growth-inhibitory effect of CFP1 loss. Our study further demonstrated that CRL4 inactivation reduced CFP1 transcription and trimethylation on lysine 4 of histone H3, which in turn inhibited cell proliferation and induced apoptosis. Therefore, CRL4 constitutes a druggable target in ovarian cancer. Citation Format: Liu-qing Yang, Han-yin Hu, Yao Han, Heng-Yan Zhu, Xiao-min Wang, Lei Ao, Ying Xu, Xuan Huang, Xuan Che, Li-Zhong Wang, Ya-Bo Jiang, Chun-wei Xu, Shu-Qun Cheng, Michal Heger, Wei-wei Pan. CpG binding protein promotes cell proliferation through H3K4 methylation in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 130.