HDAC7 regulates histone 3 lysine 27 acetylation and transcriptional activity at super-enhancer-associated genes in breast cancer stem cells

Corrado Caslini,Yuguang J Ban,Tan A Ince,Xi S Chen,Sunhwa Hong

doi:10.1038/s41388-019-0897-0

Corrado Caslini, Yuguang J Ban + Show 3 more

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https://doi.org/10.1038/s41388-019-0897-0

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Abstract

Chromatin regulation through histone modifications plays an essential role in coordinated expression of multiple genes. Alterations in chromatin induced by histone modifiers and readers regulate critical transcriptional programs involved in both normal development and tumor differentiation. Recently, we identified that histone deacetylases HDAC1 and HDAC7 are necessary to maintain cancer stem cells (CSCs) in both breast and ovarian tumors. Here, we sought to investigate the CSC-specific function of HDAC1 and HDAC7 mechanistically by using a stem-like breast cancer (BrCa) cell model BPLER and matched nonstem tumor cell (nsTC)-like HMLER, along with conventional BrCa cell lines with different CSC enrichment levels. We found that HDAC1 and HDAC3 inhibition or knockdown results in HDAC7 downregulation, which is associated with a decrease in histone 3 lysine 27 acetylation (H3K27ac) at transcription start sites (TSS) and super-enhancers (SEs) prominently in stem-like BrCa cells. Importantly, these changes in chromatin landscape also correlate with the repression of many SE-associated oncogenes, including c-MYC, CD44, CDKN1B, SLUG, VDR, SMAD3, VEGFA, and XBP1. In stem-like BrCa cells, HDAC7 binds near TSS and to SEs of these oncogenes where it appears to contribute to both H3K27ac and transcriptional regulation. These results suggest that HDAC7 inactivation, directly or through inhibition of HDAC1 and HDAC3, can result in the inhibition of the CSC phenotype by downregulating multiple SE-associated oncogenes. The CSC selective nature of this mechanism and the prospect of inhibiting multiple oncogenes simultaneously makes development of HDAC7 specific inhibitors a compelling objective.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.We previously identified a cancer stem cell (CSC)-specific function for the histone deacetylases HDAC1 and HDAC7 in breast and ovarian cancer cells
We found that MS-275 (Entinostat), which is a HDAC1 and HDAC3 specific inhibitor, downregulates HDAC7 mRNA and protein in CSC-like BPLER cells
The mechanistic model we elaborate in this study (Fig. 8) is emerging from multiple comparisons that contrast the function of different HDAC isoforms (HDAC7 vs. HDAC1/3), the role of the cellular context, chromatin markers (H3 vs. H3K27ac) and SE vs. genomewide patterns

Summary

Introduction

We previously identified a cancer stem cell (CSC)-specific function for the histone deacetylases HDAC1 and HDAC7 in breast and ovarian cancer cells. Our results demonstrated that both HDAC1 and HDAC7 are necessary to maintain CSCs. HDAC7 overexpression alone was sufficient to augment the CSC phenotype [1]. We showed that HDAC1 and/or HDAC7 inhibition downregulates stem cell markers CD44, CD49f, CD326, CD166, and BMI-1 in ten different breast, ovary, and colon cell lines and using six different HDAC inhibitors (HDACis). HDAC1 and/or HDAC7 siRNA knockdown and inhibition by HDACis, reduced 3D tumor sphere formation more significantly compared with 2D proliferation in vitro, and xenograft tumor growth in vivo [1]

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