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 UnderhillRichard M. Myers, Tadashi Kondo, Le Su

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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.

Original languageEnglish
Pages (from-to)43-54
Number of pages12
JournaliScience
Volume13
DOIs
Publication statusPublished - Mar 29 2019
Externally publishedYes

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Patel, N., Wang, J., Shiozawa, K., Jones, K. B., Zhang, Y., Prokop, J. W., ... Su, L. (2019). HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression. iScience, 13, 43-54. https://doi.org/10.1016/j.isci.2019.02.008