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

Abstract

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.

MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

“…N-Acetyl-L-cysteine (NAC) was also obtained from Sigma. HDACi and NAC were dissolved in dimethyl sulfoxide and added to the cell culture medium as described (22).…”

“…Because of their role in promoting various cancers, inhibitors of BMI1 and EZH2 are of clinical importance. Recently, we and others have shown that the expression of the PcG proteins is inhibited by histone deacetylase inhibitors (HDACi) (22). HDACi transcrip-tionally regulate expression of genes involved in proliferation control and tumorigenesis, which results in inhibition of the oncogenic phenotype and induction of cell cycle arrest, autophagy, cell death, differentiation, and cellular senescence in cancer cells (26).…”

“…In addition to cellular senescence, BMI1 also promotes cancer stem cell phenotype and therapy resistance in cancer cells (11,21). In addition to p16, BMI1 is known to regulate expression of other cancer and aging relevant genes, such as p57, and genes involved in TGF-␤ signaling, endoplasmic reticulum stress, and WNT pathways (22)(23)(24)(25). Because of their role in promoting various cancers, inhibitors of BMI1 and EZH2 are of clinical importance.…”

Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

“…Accordingly, AML1/ETO which is present in about 12% of AML cases is ETO-positive hematopoietic cells and, by another group, in various breast cancer cell lines. 34 Downregulation of c-MYC by DACi has been reported previously [35][36][37][38] and may also account for inhibition of LSC capacity. Here, a reduced protein level of c-MYC was recognized as early as 6 h after addition of DACi (data not shown), suggesting that c-MYC repression is a direct effect of DACi treatment.…”

“…In contrast, the regulation of the c-MYC target gene BMI1 13 by DACi was found to be indirect and independent from c-MYC in breast cancer. 34 Further studies will have to show if BMI1 is a direct target of c-MYC in our leukemic models.…”