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Genome-wide analysis of histone 3 lysine K27 acetylation in stem-like breast cancer cells in response to HDAC1/3/7 inhibition.

ABSTRACT: We sought to investigate the effects of HDAC1 and HDAC7 inhibition on genome-wide histone 3 lysine 27 acetylation (H3K27ac) in BPLER cells, a stem-like breast cancer (BrCa) cell model (please search for keyword "BPLER" in GEO to access over 30 associated datasets). Treatment of BPLER cells with MS-275 (Entinostat), a HDAC1 and HDAC3 specific inhibitor, specifically downregulates HDAC7 mRNA and protein. We carried out ChIP-seq analysis in BPLER cells treated with MS-275 and found that HDAC1/3/7 inhibition is associated with a decrease in H3K27ac at transcription start sites (TSS) and super-enhancers (SE) in stem-like BrCa cells. Importantly, these changes in chromatin landscape reduced H3K27ac at many SE-associated oncogenes, including c-MYC, CD44, CDKN1B, SLUG, VDR, SMAD3, VEGFA and XBP1. Our findings suggest that inactivation of HDAC1/3-HDAC7 axis may inhibit SE-associated oncogene expression in cancer stem cells, which can be a promising pathway to target for developing novel BrCa therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131436 | GEO | 2020/02/24

REPOSITORIES: GEO

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Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting. To elucidate the transcriptome response to HDAC inhibitors of normal esophageal cells and esophageal tumor cells, total RNA was isolated from non-neoplastic esophageal epithelial cells (Het1A cells) a well as from two esophageal tumor cell lines (OE21 and OE33), respectively. Cells were treated with either MS-275, Azacytidine (AZA) or in combination of both. DMSO treatment was used as control in each case. Total RNA was isolated from cells 24 h after treatment and experiments were performed in biological triplicates.

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Genome-wide analysis of histone 3 lysine K27 acetylation in stem-like breast cancer cells in response to HDAC1/3/7 inhibition.

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