@article{a8ebf6889f97412fa1fd5a5937fe192e,
title = "HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression",
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.",
author = "Nikita Patel and Juehong Wang and Kumiko Shiozawa and Jones, {Kevin B.} and Yanfeng Zhang and Prokop, {Jeremy W.} and Davenport, {George G.} and Nihira, {Naoe T.} and Zhenyue Hao and Derek Wong and Laurel Brandsmeier and Meadows, {Sarah K.} and Sampaio, {Arthur V.} and Werff, {Ryan Vander} and Makoto Endo and Capecchi, {Mario R.} and McNagny, {Kelly M.} and Mak, {Tak W.} and Nielsen, {Torsten O.} and Underhill, {T. Michael} and Myers, {Richard M.} and Tadashi Kondo and Le Su",
note = "Funding Information: We are grateful to Dr. Genze Shao (Peking University) and Dr. Qing Zhong (University of Texas Southwestern Medical Center) for providing human MULE plasmids. This work was supported by St. Baldrick's Foundation and HudsonAlpha Foundation (to L.S.), the Canadian Cancer Society Research Institute (to T.O.N. and T.M.U.), the National Institutes of Health (NIH) K08CA138764 (to K.B.J.), and NIH K01-ES025435 (to J.W.P.). K.B.J. also received additional support from the Damon Runyon Foundation and the Paul Nabil Bustany Fund for Synovial Sarcoma Research . The costs of animal care were partially covered by a one-time investigator-initiated grant from Celgene (to M.R.C.). Funding Information: We are grateful to Dr. Genze Shao (Peking University)and Dr. Qing Zhong (University of Texas Southwestern Medical Center)for providing human MULE plasmids. This work was supported by St. Baldrick's Foundation and HudsonAlpha Foundation (to L.S.), the Canadian Cancer Society Research Institute (to T.O.N. and T.M.U.), the National Institutes of Health (NIH)K08CA138764 (to K.B.J.), and NIH K01-ES025435 (to J.W.P.). K.B.J. also received additional support from the Damon Runyon Foundation and the Paul Nabil Bustany Fund for Synovial Sarcoma Research. The costs of animal care were partially covered by a one-time investigator-initiated grant from Celgene (to M.R.C.). N.P. J.W. Y.Z. and G.G.D. designed and performed the experiments. K.S. and T.K. conducted mass spectrometry. K.B.J. Z.H. M.R.C. and T.W.M. carried out the animal studies. J.W.P. performed the structural analysis. N.T.N. assisted in characterizing MDM2-MULE interaction. D.W. A.V.S. R.V.W. M.E. K.M.M. T.O.N. and T.M.U. performed the experiments in the initial stage of this study. L.B. S.K.M. and R.M.M. guided CRISPR/Cas9 genome editing. L.S. supervised the study and wrote the manuscript with input from the other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = mar,
day = "29",
doi = "10.1016/j.isci.2019.02.008",
language = "English",
volume = "13",
pages = "43--54",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
}
