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
Affiliations
Nikita Patel
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Juehong Wang
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Kumiko Shiozawa
Division of Rare Cancer Research, National Cancer Center, Tokyo 104-0045, Japan
Kevin B. Jones
Department of Orthopaedics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Yanfeng Zhang
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Jeremy W. Prokop
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA; Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA
George G. Davenport
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Naoe T. Nihira
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Zhenyue Hao
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2C1, Canada
Derek Wong
Biomdical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Laurel Brandsmeier
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Sarah K. Meadows
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Arthur V. Sampaio
Biomdical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Ryan Vander Werff
Biomdical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Makoto Endo
Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V5Z 1M9, Canada
Mario R. Capecchi
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
Kelly M. McNagny
Biomdical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Tak W. Mak
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2C1, Canada
Torsten O. Nielsen
Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V5Z 1M9, Canada
T. Michael Underhill
Biomdical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Richard M. Myers
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Tadashi Kondo
Division of Rare Cancer Research, National Cancer Center, Tokyo 104-0045, Japan
Le Su
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA; Corresponding author
Summary: 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; Molecular Biology; Cancer Subject Areas: Biological Sciences, Molecular Biology, Cancer
