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

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Version 3 2021-09-01, 14:40
Version 2 2018-07-23, 19:13
Version 1 2018-06-09, 07:13
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posted on 2021-09-01, 14:40 authored by Yu Kong, Chunbo Ai, Feng Dong, Xianyou Xia, Xiujuan Zhao, Chao Yang, Chunsheng Kang, Yan Zhou, Qian Zhao, Xiujing Sun, Xudong Wu

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.

Funding

This work was supported by the Ministry of Science and Technology of the People’s Republic of China [2016YFC0902502];Ministry of Science and Technology of the People’s Republic of China [2017YFA0504102];National Natural Science Foundation of China [31570774];National Natural Science Foundation of China [81772676];National Natural Science Foundation of China [81500258];Natural Science Foundation of Tianjin City [16JCQNJC10300];Natural Science Foundation of Tianjin City [16JCQNJC12100];Natural Science Foundation of China [81500170].

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