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

Academic Article


  • 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.
  • Published In

  • iScience  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 646415
  • Author List

  • Patel N; Wang J; Shiozawa K; Jones KB; Zhang Y; Prokop JW; Davenport GG; Nihira NT; Hao Z; Wong D
  • Start Page

  • 43
  • End Page

  • 54
  • Volume

  • 13