Targeting of BMI-1 with PTC-209 inhibits glioblastoma development

作者：Yu Kong, Chunbo Ai, Feng Dong, Xianyou Xia, Xiujuan Zhao, Chao Yang, Chunsheng Kang, Yan Zhou, Qian Zhao, Xiujing Sun, Xudong Wu · 发表于：Cell Cycle · 年份：2018 · DOI：10.1080/15384101.2018.1469872 · 被引用次数：43 · 研究领域：Epigenetics and DNA Methylation、Glioma Diagnosis and Treatment、Cancer Genomics and Diagnostics

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and refractory to existing therapies. The oncogene BMI-1, a member of Polycomb Repressive Complex 1 (PRC1) plays essential roles in various human cancers and becomes an attractive therapeutic target. Here we showed that BMI-1 is highly expressed in GBM and especially enriched in glioblastoma stem cells (GSCs). Then we comprehensively investigated the anti-GBM effects of PTC-209, a novel specific inhibitor of BMI-1. We found that PTC-209 efficiently downregulates BMI-1 expression and the histone H2AK119ub1 levels at microM concentrations. In vitro, PTC-209 effectively inhibits glioblastoma cell proliferation and migration, and GSC self-renewal. Transcriptomic analyses of TCGA datasets of glioblastoma and PTC-209-treated GBM cells demonstrate that PTC-209 reverses the altered transcriptional program associated with BMI-1 overexpression. And Chromatin Immunoprecipitation assay confirms that the derepressed tumor suppressor genes belong to BMI-1 targets and the enrichment levels of H2AK119ub1 at their promoters is decreased upon PTC-209 treatment. Strikingly, the glioblastoma growth is significantly attenuated by PTC-209 in a murine orthotopic xenograft model. Therefore our study provides proof-of-concept for inhibitors targeting BMI-1 in potential applications as an anti-GBM therapy.