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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.

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


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.


Biological Sciences; Cancer; Molecular Biology

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