Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis.

ABSTRACT: HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. In

SUBMITTER: Cheng C 

PROVIDER: S-EPMC10985028 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature