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

Nikita Patel; Juehong Wang; Kumiko Shiozawa; Kevin B Jones; Yanfeng Zhang; Jeremy W Prokop; George G Davenport; Naoe T Nihira; Zhenyue Hao; Derek Wong; Laurel Brandsmeier; Sarah K Meadows; Arthur V Sampaio; Ryan Vander Werff; Makoto Endo; Mario R Capecchi; Kelly M McNagny; Tak W Mak; Torsten O Nielsen; T Michael Underhill; Richard M Myers; Tadashi Kondo; Le Su

doi:10.1016/j.isci.2019.02.008

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

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

Authors

Nikita Patel¹, Juehong Wang¹, Kumiko Shiozawa², Kevin B Jones³, Yanfeng Zhang¹, Jeremy W Prokop⁴, George G Davenport¹, Naoe T Nihira⁵, Zhenyue Hao⁶, Derek Wong⁷, Laurel Brandsmeier¹, Sarah K Meadows¹, Arthur V Sampaio⁷, Ryan Vander Werff⁷, Makoto Endo⁸, Mario R Capecchi⁹, Kelly M McNagny⁷, Tak W Mak⁶, Torsten O Nielsen⁸, T Michael Underhill⁷, Richard M Myers¹, Tadashi Kondo², Le Su¹⁰

Affiliations

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.

Abstract

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