The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors.
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.
Bommi
Prashant V
PV
Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL, USA.
Dimri
Manjari
M
Sahasrabuddhe
Anagh A
AA
Khandekar
Janardan
J
Dimri
Goberdhan P
GP
D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000166:cytology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
C069077:BMI1 protein, human; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; D008239:Lysine