Targeting of BMI-1 with PTC-209 inhibits glioblastoma development. Issue 10 (19th May 2018)

• Record Type: Journal Article
• Authors: Kong, Yu; Ai, Chunbo; Dong, Feng; Xia, Xianyou; Zhao, Xiujuan; Yang, Chao; Kang, Chunsheng; Zhou, Yan; Zhao, Qian; Sun, Xiujing; Wu, Xudong
• Is Part Of: Cell cycle. Volume 17:Issue 10(2018)
• Page Start: 1199
• Page End: 1211
• Publication Date: 2018-05-19
• Subjects: BMI-1 -- glioblastoma -- inhibitors; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2018.1469872
• Languages: English
• ISSNs: 1538-4101

Abstract

ABSTRACT: 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.