title: Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells.
abstract: Members of the bromodomain and extra-C terminal (BET) domain protein family and the histone deacetylase (HDAC) enzyme family regulate the expression of important oncogenes and tumor suppressor genes. Here we show that the BET inhibitor JQ1 inhibits proliferation and induces apoptosis of both triple negative and estrogen receptor positive breast cancer cells. Consistent with the critical role of histone acetylation in the regulation of gene expression, treatment with JQ1 or the HDAC inhibitor mocetinostat was associated with global changes in gene expression resulting in suppression of genes involved in cell-cycle regulation. Combining JQ1 with mocetinostat, further decreased cell viability. This synergistic effect was associated with increased suppression of genes essential for cell-cycle progression. Furthermore, we detected dramatic increase in the expression of several members of the ubiquitin-specific protease 17 (USP17) family of deubiquitinating enzymes in response to the combination treatment. Increased expression of USP17 enzymes were able to attenuate the Ras/MAPK pathway causing decrease in cell viability, while, siRNA mediated depletion of USP17 significantly decreased cytotoxicity after the combination treatment. In conclusion, our study demonstrates that co-treatment with BET inhibitors and HDAC inhibitors reduces breast cancer cell viability through induction of USP17.
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition, Novum, Huddinge, Sweden.|Current address: Swetox & Karolinska Institutet, Unit for Toxicology Sciences, Södertälje, Sweden.
authors.forename: Gabor
authors.initials: G
authors.lastname: Borbely
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition, Novum, Huddinge, Sweden.
authors.forename: Lars-Arne
authors.initials: LA
authors.lastname: Haldosen
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition, Novum, Huddinge, Sweden.|SciLifeLab, Karolinska Institutet, Solna, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition, Novum, Huddinge, Sweden.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
mesh_terms: D001381:Azepines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D010450:Endopeptidases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D001549:Benzamides; D018797:Cell Cycle Proteins; D010450:Endopeptidases; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C523184:mocetinostat; C484854:USP17L2 protein, human
keywords: BET; HDAC; breast cancer; combined treatment; epigenetics