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iScience. 2019 Mar 29;13:43-54. doi: 10.1016/j.isci.2019.02.008. Epub 2019 Feb 15.

HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression.

Author information

1
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
2
Division of Rare Cancer Research, National Cancer Center, Tokyo 104-0045, Japan.
3
Department of Orthopaedics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
4
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA; Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA.
5
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
6
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2C1, Canada.
7
Biomdical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
8
Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V5Z 1M9, Canada.
9
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
10
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: lsu@hudsonalpha.org.

Abstract

Histone deacetylases (HDACs) are promising targets for cancer therapy, although their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in the regulation of MDM2 acetylation at previously uncharacterized lysines. Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 ubiquitin ligase E3 (MULE). This mechanism further reveals a therapeutic connection between the MULE ubiquitin ligase function and tumor suppression. Specifically, we show that HDAC inhibitor treatment promotes the accumulation of MULE, which diminishes the t(X; 18) translocation-associated synovial sarcomagenesis by directly targeting the fusion product SS18-SSX for degradation. These results uncover a new HDAC2-dependent pathway that integrates reversible acetylation signaling to the anticancer ubiquitin response.

KEYWORDS:

Biological Sciences; Cancer; Molecular Biology

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