Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis
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 deubi...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-04-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221138352400008X |
| _version_ | 1797248334487879680 |
|---|---|
| author | Can Cheng Hanhui Yao Heng Li Jingwen Liu Zhengyi Liu Yang Wu Liang Zhu Hejie Hu Zhengdong Fang Liang Wu |
| author_facet | Can Cheng Hanhui Yao Heng Li Jingwen Liu Zhengyi Liu Yang Wu Liang Zhu Hejie Hu Zhengdong Fang Liang Wu |
| author_sort | Can Cheng |
| collection | DOAJ |
| description | 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. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization 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 regulatory 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. |
| first_indexed | 2024-04-24T20:12:56Z |
| format | Article |
| id | doaj.art-42afa62e871648bdbf3a72b745f781e9 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-24T20:12:56Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-42afa62e871648bdbf3a72b745f781e92024-03-23T06:24:06ZengElsevierActa Pharmaceutica Sinica B2211-38352024-04-0114416241643Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasisCan Cheng0Hanhui Yao1Heng Li2Jingwen Liu3Zhengyi Liu4Yang Wu5Liang Zhu6Hejie Hu7Zhengdong Fang8Liang Wu9Department 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, ChinaDepartment 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, ChinaAnhui 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, ChinaAnhui 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, ChinaDepartment of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, ChinaDepartment 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, ChinaDepartment of General Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, ChinaDepartment 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; Corresponding authors.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; Corresponding authors.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; Corresponding authors.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. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization 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 regulatory 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.http://www.sciencedirect.com/science/article/pii/S221138352400008XColorectal cancerInvasion and metastasisPost-translational modificationUbiquitinationSUMOylationUSP48 |
| spellingShingle | Can Cheng Hanhui Yao Heng Li Jingwen Liu Zhengyi Liu Yang Wu Liang Zhu Hejie Hu Zhengdong Fang Liang Wu Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis Acta Pharmaceutica Sinica B Colorectal cancer Invasion and metastasis Post-translational modification Ubiquitination SUMOylation USP48 |
| title | Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis |
| title_full | Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis |
| title_fullStr | Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis |
| title_full_unstemmed | Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis |
| title_short | Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis |
| title_sort | blockade of the deubiquitinating enzyme usp48 degrades oncogenic hmga2 and inhibits colorectal cancer invasion and metastasis |
| topic | Colorectal cancer Invasion and metastasis Post-translational modification Ubiquitination SUMOylation USP48 |
| url | http://www.sciencedirect.com/science/article/pii/S221138352400008X |
| work_keys_str_mv | AT cancheng blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT hanhuiyao blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT hengli blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT jingwenliu blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT zhengyiliu blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT yangwu blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT liangzhu blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT hejiehu blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT zhengdongfang blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis AT liangwu blockadeofthedeubiquitinatingenzymeusp48degradesoncogenichmga2andinhibitscolorectalcancerinvasionandmetastasis |