USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B.
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.
['Lan|Xianjiang|X|', 'Atanassov|Boyko S|BS|', 'Li|Wenqian|W|', 'Zhang|Ying|Y|', 'Florens|Laurence|L|', 'Mohan|Ryan D|RD|', 'Galardy|Paul J|PJ|', 'Washburn|Michael P|MP|', 'Workman|Jerry L|JL|', 'Dent|Sharon Y R|SYR|']
D045744:Cell Line, Tumor D057809:HEK293 Cells D006657:Histones D006801:Humans D009361:Neoplasm Invasiveness D009687:Nuclear Proteins D056971:Nuclear Receptor Co-Repressor 1 D011485:Protein Binding D021122:Protein Subunits D018160:Receptors, Cytoplasmic and Nuclear D012097:Repressor Proteins D015293:Transducin D043222:Ubiquitin Thiolesterase D064570:Ubiquitin-Specific Proteases D054875:Ubiquitination D000071678:WD40 Repeats
USP44 N-CoR breast cancer H2B ubiquitination transcription