HDAC2 regulates site-specific acetylation of MDM2 and its ubiquitination signaling in tumor suppression

ABSTRACT: Histone deacetylases (HDACs) are promising targets for cancer therapy, while their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in 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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Le Su 

PROVIDER: PXD012540 | JPOST Repository | Sun Mar 22 00:00:00 GMT 2020

REPOSITORIES: jPOST