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.

组蛋白脱乙酰基酶（HDACs）是癌症治疗的有希望的靶标，尽管其各自的作用尚不完全清楚。在这里，我们确定了HDAC2在以前未表征的赖氨酸MDM2乙酰化调节中的作用。HDAC2失活后，这种乙酰化作用会在MDM2的富含赖氨酸的域中产生结构信号，以防止其下游底物MCL-1泛素连接酶E3（MULE）的识别和降解。该机制进一步揭示了MULE泛素连接酶功能与肿瘤抑制之间的治疗联系。具体而言，我们表明，HDAC抑制剂治疗可通过直接靶向融合产物SS18-SSX降解来促进MULE的积累，从而减少t（X; 18）易位相关的滑膜肉瘤的发生。