title: 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.
authors: Department of Genetics, Yale University, School of Medicine, New Haven, CT 06520-8005, USA.
authors: Y J
authors: YJ
authors: Kim
authors: C B
authors: CB
authors: Greer
authors: K R
authors: KR
authors: Cecchini
authors: L N
authors: LN
authors: Harris
authors: D P
authors: DP
authors: Tuck
authors: T H
authors: TH
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D015894:Genome, Human; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D061805:Transcription Elongation, Genetic / Q000187:drug effects*; D061785:Transcription Initiation, Genetic; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012319:RNA Polymerase II; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C012589:trichostatin A; C508053:ERBB2 protein, human