title: BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses.
abstract: Control of histone acetylation is a part of the epigenetic mechanism that regulates gene expression and chromatin architecture. The members of the bromodomain and extra terminal domain (BET) protein family are a group of epigenetic readers that recognize histone acetylation, whereas histone deacetyl- ases such as sirtuin 1 (SIRT1) function as epigenetic erasers. We observed that BET inhibition by the specific inhibitor JQ1 upregulated SIRT1 expression and activated SIRT1. Moreover, we observed that BET inhibition functionally reversed the pro-inflammatory effect of SIRT1 inhibition in a cellular lung disease model. SIRT1 activation is desirable in many age-related, metabolic and inflammatory diseases; our results suggest that BET protein inhibition would be beneficial in treatment of those conditions. Most importantly, our findings demonstrate a novel mechanism of SIRT1 activation by inhibition of the BET proteins.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland. tarja.kokkola@uef.fi.|Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland. tarja.kokkola@uef.fi.
authors.forename: Tarja
authors.initials: T
authors.lastname: Kokkola
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Suuronen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Pesonen
authors.affiliation: Structural Genomics Consortium, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.affiliation: Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
authors.forename: Elina M
authors.initials: EM
authors.lastname: Jarho
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D061986:MCF-7 Cells; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics* / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D014230:Triazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human
keywords: SIRT1; acetylation; bromodomain and extra terminal domain protein; cancer; epigenetics; gene expression