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HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade.

ABSTRACT: Treatment with histone deacetylase inhibitors (HDACI) results in potent cytotoxicity of a variety of cancer cell types, and these drugs are used clinically to treat hematological tumors. They are known to repress the transcription of ERBB2 and many other oncogenes, but little is known about this mechanism. Using global run-on sequencing (GRO-seq) to measure nascent transcription, we find that HDACI cause transcriptional repression by blocking RNA polymerase II elongation. Our data show that HDACI preferentially repress the transcription of highly expressed genes as well as high copy number genes in HER2+ breast cancer genomes. In contrast, genes that are activated by HDACI are moderately expressed. We analyzed gene copy number in combination with microarray and GRO-seq analysis of expression level, in normal and breast cancer cells to show that high copy number genes are more likely to be repressed by HDACI than non-amplified genes. The inhibition of transcription of amplified oncogenes, which promote survival and proliferation of cancer cells, might explain the cancer-specific lethality of HDACI, and may represent a general therapeutic strategy for cancer.

SUBMITTER: Kim YJ

PROVIDER: S-EPMC3676447 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade.

Kim Y J YJ Greer C B CB Cecchini K R KR Harris L N LN Tuck D P DP Kim T H TH

Oncogene 20130225 23

Treatment with histone deacetylase inhibitors (HDACI) results in potent cytotoxicity of a variety of cancer cell types, and these drugs are used clinically to treat hematological tumors. They are known to repress the transcription of ERBB2 and many other oncogenes, but little is known about this mechanism. Using global run-on sequencing (GRO-seq) to measure nascent transcription, we find that HDACI cause transcriptional repression by blocking RNA polymerase II elongation. Our data show that HDAC ...[more]

PMID: 23435418

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Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compounds that target the epigenome for the treatment of cancer. This notion is supported by biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through association with oncogenic fusion proteins such as PML-RARα and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biological and molecular responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific molecules and pathways in the tumor-selective cytotoxic activity of these compounds.

Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARM-NM-1 and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds. Whole genome expression profiling was performed for vorinostat-treated samples and control samples (DMSO vehicle control). Fourteen samples were included in this study. Each sample has three biological replicates, making forty-two arrays in total.

Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARα and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds.

Dataset Information

HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade.

Publications

HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade.

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