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

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

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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 iden-tify 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 un-dergoes 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 pharmacolog-ical inhibitor of USP48.Interestingly,the small-molecule inhibitor targeting USP48 induces destabiliza-tion of HMGA2.Clinically,upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer(CRC).Collectively,our study not only elucidates the reg-ulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC,but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

Colorectal cancerInvasion and metastasisPost-translational modificationUbiquitinationSUMOylationUSP48HMGA2Specific inhibitors

Can Cheng、Hanhui Yao、Heng Li、Jingwen Liu、Zhengyi Liu、Yang Wu、Liang Zhu、Hejie Hu、Zhengdong Fang、Liang Wu

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Department of General Surgery,the First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230001,China

Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery,the First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230001,China

Department of Comprehensive Surgery,Anhui Provincial Cancer Hospital,West District of the First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230001,China

Anhui Provincial Hospital Health Management Center,the First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230001,China

Department of Breast Surgery,Henan Provincial People's Hospital,People's Hospital of Zhengzhou University,People's Hospital of Henan University,Zhengzhou 450003,China

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国家自然科学基金中央高校基本科研业务费专项安徽省自然科学基金中国博士后科学基金

82103543WK91100001592108085QH3402021M693082

2024

10.1016/j.apsb.2024.01.006

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(4)
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