title: USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B.
abstract: Decreased expression of the USP44 deubiquitinase has been associated with global increases in H2Bub1 levels during mouse embryonic stem cell (mESC) differentiation. However, whether USP44 directly deubiquitinates histone H2B or how its activity is targeted to chromatin is not known. We identified USP44 as an integral subunit of the nuclear receptor co-repressor (N-CoR) complex. USP44 within N-CoR deubiquitinates H2B in vitro and in vivo, and ablation of USP44 impairs the repressive activity of the N-CoR complex. Chromatin immunoprecipitation (ChIP) experiments confirmed that USP44 recruitment reduces H2Bub1 levels at N-CoR target loci. Furthermore, high expression of USP44 correlates with reduced levels of H2Bub1 in the breast cancer cell line MDA-MB-231. Depletion of either USP44 or TBL1XR1 impairs the invasiveness of MDA-MB-231 cells in vitro and causes an increase of global H2Bub1 levels. Our findings indicate that USP44 contributes to N-CoR functions in regulating gene expression and is required for efficient invasiveness of triple-negative breast cancer cells.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Xianjiang
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Boyko S
authors.initials: BS
authors.lastname: Atanassov
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Li
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: University of Missouri-Kansas City, Kansas City, MO 64110, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Mohan
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Galardy
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Workman
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: sroth@mdanderson.org.
authors.forename: Sharon Y R
authors.initials: SYR
authors.lastname: Dent
mesh_terms: D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D015293:Transducin / Q000737:chemistry / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination; D000071678:WD40 Repeats
chemical_list: D006657:Histones; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C119542:TBL1X protein, human; C473691:TBL1XR1 protein, human; C579216:USP44 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D015293:Transducin
keywords: H2B ubiquitination; N-CoR; USP44; breast cancer; transcription