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

• DOI: 10.1016/j.apsb.2024.01.006
• Publication Date: 2024-01-17T08:48:49Z
• Authors: Can Cheng; Hanhui Yao; Heng Li; Jingwen Liu; Zhengyi Liu; Yang Wu; Liang Zhu; Hejie Hu; Zhengdong Fang; Liang Wu
• Keywords: HMGA2; Deubiquitinating enzyme

HMGA2, a pivotal transcription factor, functions as 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 and USP48 identified deubiquitinating enzyme HMGA2. The enforced expression significantly increased HMGA2 protein levels by inhibiting its degradation, while deprivation promoted thereby suppressing tumor invasion metastasis. We discovered undergoes SUMOylation at lysine 258, which enhances binding affinity Through subsequent phenotypic screening small molecules, we DUB-IN-2 remarkably potent pharmacological inhibitor USP48. Interestingly, small-molecule targeting induces destabilization Clinically, upregulation or cancerous tissues is indicative poor prognosis for patients colorectal cancer (CRC). Collectively, our study not only elucidates regulatory mechanism DUBs involved stability validates potential therapeutic target CRC, but also identifies promising candidate CRC treatment.