HDAC inhibitors repress the polycomb protein BMI1

Abstract

Control of gene expression is governed by a highly complex network of epigenetic processes, including histone acetylation, histone methylation, DNA methylation, and chromatin remodeling complexes, among others.1 Because transformed cells characteristically display silencing of genes involved in cell death and differentiation, intense efforts have focused on interventions capable of reversing these processes. These have led to the clinical development of histone deacetylase inhibitors (HDACIs), which promote acetylation of histone tails, reversal of chromatin condensation, and reexpression of repressed genes,2 as well as DNA methyltransferase inhibitors (DNMTIs), which reverse gene silencing by preventing repressive methylation of DNA CpG islands.1 HDACIs and DNMTIs have been approved for the treatment of patients with cutaneous T-cell lymphoma and myelodysplastic syndrome respectively.3 The mechanism by which HDACIs trigger cell death in transformed cells remains the subject of continuing debate. In addition to triggering reexpression of death-related genes, HDACIs also acetylate numerous proteins,4 including Hsp90 and Ku70, as well as transcription factors, all of which can contribute to lethality.5 HDACIs also cooperate with other epigenetically acting agents such as DNMTIs, leading to synergistic induction of cell death.6 Several recent studies suggest that HDACI lethality may involve perturbations in the expression or activity of various repressive complexes, particularly those implicated in histone methylation. For example, polycomb proteins such as BMI1 and EZH2 form complexes responsible for the formation of repressive histone methylation marks (e.g., trimethylation of H3K27). In human leukemia cells, HDACIs downregulate EZH2 in association with cell death induction.7 However, the relationship between HDAC inhibition and expression of BMI1, a protein implicated in stem cell maintenance, has not been explored. In an elegant study by Prashant et al. in Cell Cycle, the authors investigated the effects of HDACIs on BMI1 expression and downstream targets in human breast cancer cells. They found that exposure of cells to various HDACIs resulted in marked downregulation of BMI1 (and EZH2) through a transcriptional mechanism, accompanied by diminished activity of BMI1-related polycomb repressive complexes, manifested by diminished trimethylation of H3K27, a classic repressive mark. These events were accompanied by re-expression of growth inhibitory proteins and putative tumor suppressor genes, resulting in cell death by apoptosis or senescence. The authors conclude that among their numerous lethal actions, HDACIs may trigger transformed cell death by downregulating BMI1 and diminishing its repressive effects on critical tumor suppressor genes, loss of which contributes to the neoplastic phenotype. The findings of this study have potentially important implications for our understanding of the mechanism of action of HDACIs, as well as the rational use of this important class of antineoplastic agents. While conventional wisdom holds that HDACIs act by opposing chromatin condensation and permitting re-expression of cell death- and differentiation-related genes, it is now very clear that their mode of action is highly pleiotropic, and can involve both epigenetic and non-epigenetic processes. The latter include disruption of proteasome and chaperone protein function, induction of oxidative injury, upregulation of death receptors, and induction of DNA damage, among numerous others.2,5 HDACIs also downregulate numerous genes, which in the case of pro-survival genes, could plausibly contribute to cell death.2 HDACI-mediated upregulation of gene expression may occur through direct mechanisms, e.g., acetylation of gene promoter regions, or by indirect mechanisms, e.g., acetylation/activation of transcription factors or as now shown in the study by Prashant et al., by downregulating the expression of proteins like BMI1 involved in repressive complexes. These observations could have a significant impact on rational approaches to combination therapy involving HDACIs. Recently, attention has focused on novel epigenetic agents other than HDACIs or DNMTIs i.e., inhibitors of histone methyltransferases (HMTs) or histone demethylases.8,9 Indeed, recent studies have described agents that target HMTs (e.g., 3-deazaneplanocin), and have shown synergistic interactions with HDACIs.7 The identification of the repressive polycomb protein BMI1 as another target of HDACIs has clear implications for rational combination studies employing this class of agents. Finally, the importance of BMI1 in tumor stem cell renewal and maintenance10 could have extremely significant implications for the therapeutic potential of HDACI-containing regimens. Given continuing interest in the HDACI field, it is likely that these and related questions will be answered in the years to come.