SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity
Abstract ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the I...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-03-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01194-2 |
| _version_ | 1797220026040713216 |
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| author | Ji An Kang Yoon Jung Kim Kyu Yun Jang Hye Won Moon Haeseung Lee Seonjeong Lee Hyun Kyu Song Sang Woo Cho Yoon Sun Yoo Hye Gyeong Han Min-Ju Kim Myoung Ja Chung Cheol Yong Choi Cheolju Lee Chaeuk Chung Gang Min Hur You-Sun Kim Young Joo Jeon |
| author_facet | Ji An Kang Yoon Jung Kim Kyu Yun Jang Hye Won Moon Haeseung Lee Seonjeong Lee Hyun Kyu Song Sang Woo Cho Yoon Sun Yoo Hye Gyeong Han Min-Ju Kim Myoung Ja Chung Cheol Yong Choi Cheolju Lee Chaeuk Chung Gang Min Hur You-Sun Kim Young Joo Jeon |
| author_sort | Ji An Kang |
| collection | DOAJ |
| description | Abstract ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the ISG15 target repertoire. Here, we identified SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, as a new target for ISGylation. SIRT1 ISGylation impairs the association of SIRT1 with its negative regulator, deleted in breast cancer 1 (DBC1), which unleashes SIRT1 from its inactive state and leads to an increase in its deacetylase activity. Importantly, SIRT1 ISGylation promoted lung cancer progression and limited lung cancer cell sensitivity to DNA damage-based therapeutics in vivo and in vitro models. The levels of ISG15 mRNA and protein were significantly higher in lung cancer tissues than in adjacent normal tissues. Accordingly, elevated expression of SIRT1 and ISG15 was associated with poor prognosis in lung cancer patients, a finding that could be translated for lung cancer patient stratification and disease outcome evaluation. Taken together, our findings provide a mechanistic understanding of the regulatory effect of SIRT1 ISGylation on tumor progression and therapeutic efficacy in lung cancer. |
| first_indexed | 2024-04-24T12:42:59Z |
| format | Article |
| id | doaj.art-c826fa42999847ed9a55a5d0b1f2311b |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-04-24T12:42:59Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-c826fa42999847ed9a55a5d0b1f2311b2024-04-07T11:09:32ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132024-03-0156365667310.1038/s12276-024-01194-2SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activityJi An Kang0Yoon Jung Kim1Kyu Yun Jang2Hye Won Moon3Haeseung Lee4Seonjeong Lee5Hyun Kyu Song6Sang Woo Cho7Yoon Sun Yoo8Hye Gyeong Han9Min-Ju Kim10Myoung Ja Chung11Cheol Yong Choi12Cheolju Lee13Chaeuk Chung14Gang Min Hur15You-Sun Kim16Young Joo Jeon17Department of Biochemistry, Chungnam National University College of MedicineDepartment of Biochemistry, Chungnam National University College of MedicineDepartment of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital and Research Institute for Endocrine SciencesDepartment of Biochemistry, Chungnam National University College of MedicineCollege of Pharmacy, Pusan National UniversityChemical & Biological Integrative Research Center, Korea Institute of Science and TechnologyDepartment of Life Sciences, Korea UniversityDepartment of Biological Sciences, Sungkyunkwan UniversityDepartment of Biochemistry, Chungnam National University College of MedicineDepartment of Biochemistry, Chungnam National University College of MedicineCollege of Pharmacy, Pusan National UniversityDepartment of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital and Research Institute for Endocrine SciencesDepartment of Biological Sciences, Sungkyunkwan UniversityChemical & Biological Integrative Research Center, Korea Institute of Science and TechnologyDivision of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National UniversityDepartment of Pharmacology, Chungnam National University College of MedicineDepartment of Biochemistry, Ajou University, School of Medicine & Department of Biomedical Sciences, Graduate School, Ajou UniversityDepartment of Biochemistry, Chungnam National University College of MedicineAbstract ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the ISG15 target repertoire. Here, we identified SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, as a new target for ISGylation. SIRT1 ISGylation impairs the association of SIRT1 with its negative regulator, deleted in breast cancer 1 (DBC1), which unleashes SIRT1 from its inactive state and leads to an increase in its deacetylase activity. Importantly, SIRT1 ISGylation promoted lung cancer progression and limited lung cancer cell sensitivity to DNA damage-based therapeutics in vivo and in vitro models. The levels of ISG15 mRNA and protein were significantly higher in lung cancer tissues than in adjacent normal tissues. Accordingly, elevated expression of SIRT1 and ISG15 was associated with poor prognosis in lung cancer patients, a finding that could be translated for lung cancer patient stratification and disease outcome evaluation. Taken together, our findings provide a mechanistic understanding of the regulatory effect of SIRT1 ISGylation on tumor progression and therapeutic efficacy in lung cancer.https://doi.org/10.1038/s12276-024-01194-2 |
| spellingShingle | Ji An Kang Yoon Jung Kim Kyu Yun Jang Hye Won Moon Haeseung Lee Seonjeong Lee Hyun Kyu Song Sang Woo Cho Yoon Sun Yoo Hye Gyeong Han Min-Ju Kim Myoung Ja Chung Cheol Yong Choi Cheolju Lee Chaeuk Chung Gang Min Hur You-Sun Kim Young Joo Jeon SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity Experimental and Molecular Medicine |
| title | SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity |
| title_full | SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity |
| title_fullStr | SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity |
| title_full_unstemmed | SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity |
| title_short | SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity |
| title_sort | sirt1 isgylation accelerates tumor progression by unleashing sirt1 from the inactive state to promote its deacetylase activity |
| url | https://doi.org/10.1038/s12276-024-01194-2 |
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