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Cell Rep. 2016 Nov 22;17(9):2382-2393. doi: 10.1016/j.celrep.2016.10.076.

USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B.

Author information

1
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.
2
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.
3
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
4
University of Missouri-Kansas City, Kansas City, MO 64110, USA.
5
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
6
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.
7
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.

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.

KEYWORDS:

H2B ubiquitination; N-CoR; USP44; breast cancer; transcription

PMID:
27880911
PMCID:
PMC5131803
DOI:
10.1016/j.celrep.2016.10.076
[Indexed for MEDLINE]
Free PMC Article

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