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Combinatorial pharmacological approaches target EZH2-mediated gene repression in breast cancer cells

ABSTRACT: Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously shown that S-adenosylhomocysteine hydrolase (SAHH) inhibitor 3-Deazaneplanocin A (DZNep) can modulate histone methylation and disrupt EZH2 complex. Here, we used DZNep, together with other chromatin remodeling agents, as well as RNA interference-mediated EZH2 depletion, to probe the role of EZH2 in coordination with other epigenetic components in gene regulation in breast cancer cells. Through genome-wide gene expression analysis, coupled with extensive chromatin immunoprecipitation analysis of histone modifications, we have identified a variety of gene sets that are regulated either by EZH2 alone or through the coordinated action of EZH2 with HDAC and/or DNA methylation. We further found that tumor antigen GAGEs were regulated by distinct epigenetic mechanisms in a cell context-dependent manner, possibly reflecting mechanistic heterogeneity in breast cancer. Intriguingly, we found that EZH2 regulates a remarkable cohort of genes whose functions are highly enriched in immunoresponse and autocrine inflammation network, and their transcriptional activation upon EZH2 perturbation is cancer-specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings demonstrate the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation. Keywords: Total RNA

ORGANISM(S): Homo sapiens

PROVIDER: GSE17589 | GEO | 2009/08/12

SECONDARY ACCESSION(S): PRJNA118523

REPOSITORIES: GEO

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Project description:Background:Aberrant DNA methylation that silences tumor suppressor genes occurs frequently in patients with acute myeloid leukemia (AML). Treatment of AML patients with the inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-AZA-CdR) can induce complete remissions, but most patients will relapse. The clinical efficacy of 5-AZA-CdR may be influenced by its limited capacity to activate tumor suppressor genes silenced by methylation of lysine 27 histone H3 (H3K27) by EZH2. In order to overcome this limitation, we investigated previously the antileukemic action of 5-AZA-CdR in combination with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep) on HL-60 AML cells. We observed a remarkable synergistic interaction against these AML cells for this combination. In this study, we investigated in more depth the action of 5-AZA-CdR plus DZNep on gene expression in AML cells using RNA sequence analysis Result:In a colony assay, 5-AZA-CdR in combination with DZNep exhibited also a potent synergy against another human AML cell line: AML-3. The induction of apoptosis in HL-60 and AML3 leukemic cells by 5-AZA-CdR plus DZNep was also synergistic. RNA sequence analysis on HL-60 leukemic cells showed that the combination of 5-AZA-CdR plus DZNep increased the expression of thousands of genes. The genes upregulated by this combination included genes related to differentiation, development, senescence, apoptosis, and tumor suppressor function. Many of the genes activated by 5-AZA-CdR plus DZNep have the potential to suppress leukemogenesis. Conclusion: The activation of many genes by the combination of 5-AZA-CdR plus DZNep correlates with its synergistic antileukemic action. The block in differentiation is one of the hallmarks of AML.The activation of many genes that program differentiation and development by this combination of epigenetic agents has the potential to reverse this block. The reversal of these two epigenetic genesilencing mechanisms by 5-AZA-CdR plus DZNep merits clinical investigation in patients with AML

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Combinatorial pharmacological approaches target EZH2-mediated gene repression in breast cancer cells

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