title: HDAC8 and STAT3 repress BMF gene activity in colon cancer cells.
abstract: Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to identify a direct target gene of HDAC8 repression, namely, BMF. Interestingly, the repressive role of HDAC8 could be uncoupled from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective inhibitors as therapeutic agents, beyond the reported involvement of HDAC8 in childhood malignancy.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Nian
authors.affiliation: Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rajendran
authors.affiliation: Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.affiliation: Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Dashwood
authors.affiliation: Department of Biochemistry & Molecular Biology, New York Medical College, Valhalla, NY, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Pinto
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Boardman
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Limburg
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
authors.forename: C V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: 1] Linus Pauling Institute, Oregon State University, Corvallis, OR, USA [2] Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ho
authors.affiliation: 1] Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, TX, USA [2] Department of Nutrition & Food Science, Texas A&M University, College Station, TX, USA [3] Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, TX, USA [4] Department of Molecular & Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Dashwood
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D045325:HCT116 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011773:Pyruvates / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486655:BMF protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011773:Pyruvates; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C409470:HDAC8 protein, human; D006655:Histone Deacetylases