The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors

被引:66
作者
Bommi, Prashant V. [1 ]
Dimri, Manjari [1 ]
Sahasrabuddhe, Anagh A. [1 ]
Khandekar, Janardan D. [1 ]
Dimri, Goberdhan P. [1 ]
机构
[1] NorthShore Univ HealthSystem Res Inst, Dept Med, Evanston, IL USA
关键词
HDAC inhibitors; PcG proteins; BMI1; EZH2; c-Myc; p57; breast cancer; HISTONE DEACETYLASE INHIBITORS; SUBEROYLANILIDE HYDROXAMIC ACID; SENESCENCE-LIKE STATE; C-MYC; INK4A-ARF LOCUS; CANCER CELLS; GENE; EXPRESSION; APOPTOSIS; ONCOPROTEIN;
D O I
10.4161/cc.9.13.12147
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Polycomb group (PcG) proteins are overexpressed in several human malignancies including breast cancer. In particular, aberrant expression of BMI1 and EZH2 has been linked to metastasis and poor prognosis in cancer patients. At present, very little is known about the pharmacological inhibitors of PcG proteins. Here we show that histone deacetylase inhibitors (HDACi) downregulate expression of BMI1. Treatment of MCF10A cells, which are immortal non-transformed breast epithelial cells, and breast cancer cells with HDACi led to decreased expression of BMI1. We further show that downregulation of BMI1 by HDACi results due to the transcriptional downregulation of BMI1 gene. Specifically, we show that primary transcription and promoter activity of BMI1 is suppressed upon treatment with HDACi. Furthermore, downregulation of BMI1 was accompanied by a decrease in histone 2A lysine 119 ubiquitination (H2AK119Ub), which is catalyzed by BMI1 containing polycomb repressive complex 1. HDACi treatment also led to derepression of growth inhibitory genes and putative tumor suppressors, which are known to be silenced by PcG proteins and polycomb repressive complexes (PRCs). In summary, our findings suggest that BMI1 is an important therapy target of HDACi, and that HDACi can be used alone or in combination with other therapies to inhibit growth of tumors that overexpress PcG proteins such as BMI1.
引用
收藏
页码:2663 / 2673
页数:11
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