title: The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD fingers.
abstract: The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation and is implicated in carcinogenesis. It contains multiple conserved chromatin-associated domains, including three PHD fingers of unknown function. Here, we show that the first and third, but not the second, PHD fingers of KDM5B possess histone binding activities. The PHD1 finger is highly specific for unmodified histone H3 (H3K4me0), whereas the PHD3 finger shows preference for the trimethylated histone mark H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for genes involved in inflammatory responses, cell proliferation, adhesion, and migration. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with the histone deacetylase 1 (HDAC1) in gene repression. KDM5B is downregulated in triple-negative breast cancer relative to estrogen-receptor-positive breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion, and the PHD1-H3K4me0 interaction is essential for inhibiting migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a multivalent mechanism for KDM5B-mediated transcriptional regulation.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Brianna J
authors.initials: BJ
authors.lastname: Klein
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lianhua
authors.initials: L
authors.lastname: Piao
authors.affiliation: Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Rincon-Arano
authors.affiliation: Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Danni
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.affiliation: Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Larson
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cortazar
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Pedro V
authors.initials: PV
authors.lastname: Peña
authors.affiliation: Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mangan
authors.affiliation: Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bentley
authors.affiliation: Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Radiation Oncology, University Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Groudine
authors.affiliation: Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Center for Cancer Epigenetics and Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: xbshi@mdanderson.org.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@ucdenver.edu.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; D056284:Histone Deacetylase 1; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex