The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression
Abstract Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identified ubiquitin‐specific peptidase 44 (USP44), a member of the deubiquitinase...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06358-y |
| _version_ | 1797388086669213696 |
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| author | Sisi Chen Binghai Zhou Wei Huang Qing Li Ye Yu Xiuqing Kuang Huabin Huang Wei Wang Peiyi Xie |
| author_facet | Sisi Chen Binghai Zhou Wei Huang Qing Li Ye Yu Xiuqing Kuang Huabin Huang Wei Wang Peiyi Xie |
| author_sort | Sisi Chen |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identified ubiquitin‐specific peptidase 44 (USP44), a member of the deubiquitinase family, as a novel regulator of HCC progression. The tumor suppressive function of USP44 was evaluated in a series of in vitro and in vivo experiments. Through quantitative proteomics examination, we demonstrated that USP44 inhibits HCC PDL1 expression by downregulating the Hedgehog (Hh) signaling pathway. Mechanistically, we found that USP44 directly interacts with Itch, an E3 ligase involved in Hh signaling, and promotes the deubiquitination and stabilization of Itch. These events result in the proteasomal degradation of Gli1 and subsequent inactivation of Hh signaling, which ultimately suppresses PDL1 expression and the progression of HCC. Furthermore, the HCC tissue microarray was analyzed by immunohistochemistry to evaluate the pathological relevance of the USP44/Itch/Gli1/PDL1 axis. Finally, the Gli1 inhibitor GANT61 was found to act in synergy with anti-PDL1 therapy. Overall, USP44 can act as a suppressive gene in HCC by modulating Hh signaling, and co-inhibition of Gli1 and PDL1 might be an effective novel combination strategy for treating HCC patients. |
| first_indexed | 2024-03-08T22:34:38Z |
| format | Article |
| id | doaj.art-c4a9aa23c5c448f48f1c06d279f5f92e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T22:34:38Z |
| publishDate | 2023-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c4a9aa23c5c448f48f1c06d279f5f92e2023-12-17T12:31:36ZengNature Publishing GroupCell Death and Disease2041-48892023-12-01141211310.1038/s41419-023-06358-yThe deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expressionSisi Chen0Binghai Zhou1Wei Huang2Qing Li3Ye Yu4Xiuqing Kuang5Huabin Huang6Wei Wang7Peiyi Xie8Department of Neurology, Second Affiliated Hospital of Nanchang UniversityHepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, Second Affiliated Hospital of Nanchang UniversityDepartment of Neurology, Second Affiliated Hospital of Nanchang UniversityDepartment of Pathology, Second Affiliated Hospital of Nanchang UniversityDepartment of Neurology, Second Affiliated Hospital of Nanchang UniversityDepartment of Physical Examination, Second Affiliated Hospital of Nanchang UniversityDepartment of Medical Imaging, Second Affiliated Hospital of Nanchang UniversityDepartment of Neurology, Second Affiliated Hospital of Nanchang UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of EducationAbstract Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identified ubiquitin‐specific peptidase 44 (USP44), a member of the deubiquitinase family, as a novel regulator of HCC progression. The tumor suppressive function of USP44 was evaluated in a series of in vitro and in vivo experiments. Through quantitative proteomics examination, we demonstrated that USP44 inhibits HCC PDL1 expression by downregulating the Hedgehog (Hh) signaling pathway. Mechanistically, we found that USP44 directly interacts with Itch, an E3 ligase involved in Hh signaling, and promotes the deubiquitination and stabilization of Itch. These events result in the proteasomal degradation of Gli1 and subsequent inactivation of Hh signaling, which ultimately suppresses PDL1 expression and the progression of HCC. Furthermore, the HCC tissue microarray was analyzed by immunohistochemistry to evaluate the pathological relevance of the USP44/Itch/Gli1/PDL1 axis. Finally, the Gli1 inhibitor GANT61 was found to act in synergy with anti-PDL1 therapy. Overall, USP44 can act as a suppressive gene in HCC by modulating Hh signaling, and co-inhibition of Gli1 and PDL1 might be an effective novel combination strategy for treating HCC patients.https://doi.org/10.1038/s41419-023-06358-y |
| spellingShingle | Sisi Chen Binghai Zhou Wei Huang Qing Li Ye Yu Xiuqing Kuang Huabin Huang Wei Wang Peiyi Xie The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression Cell Death and Disease |
| title | The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression |
| title_full | The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression |
| title_fullStr | The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression |
| title_full_unstemmed | The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression |
| title_short | The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression |
| title_sort | deubiquitinating enzyme usp44 suppresses hepatocellular carcinoma progression by inhibiting hedgehog signaling and pdl1 expression |
| url | https://doi.org/10.1038/s41419-023-06358-y |
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