Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin

• DOI: 10.1186/s13148-018-0605-x
• Publication Date: 2019-01-16T13:02:58Z
• Authors: Chao He; Jian Sun; Chao Liu; Yuhang Jiang; Yongqiang Hao
• Keywords: Demethylase; Histone Methylation

In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, mechanisms drug remain elusive, limiting therapeutic efficacy. Here, we set out explore relationship between dynamic histone changes and efficacy cisplatin against OS. First, found two demethylases associated with H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, KDM6B that were upregulated after treatment. Consistent clinical data, cisplatin-resistant OS specimens showed lower H3K27me3 levels than sensitive specimens. Then, evaluated effects alteration on chemosensitivity. vitro inhibition methyltransferase EZH2 in cells decreased led resistance. Conversely, KDM6A increased reversed vivo. Mechanistically, help RNA sequencing (RNAseq), PRKCA MCL1 directly participated process by altering their gene loci, ultimately inactivating RAF/ERK/MAPK cascades decreasing phosphorylation BCL2. Our study reveals a new epigenetic mechanism indicates elevated can sensitize cisplatin, suggesting promising strategy for treatment