SIRT2 promotes murine melanoma progression through natural killer cell inhibition
Abstract SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and fun...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-06-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-92445-z |
| _version_ | 1818839233292402688 |
|---|---|
| author | Manchao Zhang Scarlett Acklin John Gillenwater Wuying Du Mousumi Patra Hao Yu Bo Xu Jianhua Yu Fen Xia |
| author_facet | Manchao Zhang Scarlett Acklin John Gillenwater Wuying Du Mousumi Patra Hao Yu Bo Xu Jianhua Yu Fen Xia |
| author_sort | Manchao Zhang |
| collection | DOAJ |
| description | Abstract SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance. |
| first_indexed | 2024-12-19T03:51:02Z |
| format | Article |
| id | doaj.art-e610561f6fb24f419028b523a030e68e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T03:51:02Z |
| publishDate | 2021-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e610561f6fb24f419028b523a030e68e2022-12-21T20:37:00ZengNature PortfolioScientific Reports2045-23222021-06-0111111310.1038/s41598-021-92445-zSIRT2 promotes murine melanoma progression through natural killer cell inhibitionManchao Zhang0Scarlett Acklin1John Gillenwater2Wuying Du3Mousumi Patra4Hao Yu5Bo Xu6Jianhua Yu7Fen Xia8Department of Radiation Oncology, University of Arkansas for Medical SciencesDepartment of Radiation Oncology, University of Arkansas for Medical SciencesDepartment of Radiation Oncology, University of Arkansas for Medical SciencesDepartment of Radiation Oncology, University of Arkansas for Medical SciencesDepartment of Radiation Oncology, University of Arkansas for Medical SciencesDepartment of Radiation Oncology, University of Arkansas for Medical SciencesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research InstituteDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research InstituteDepartment of Radiation Oncology, University of Arkansas for Medical SciencesAbstract SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.https://doi.org/10.1038/s41598-021-92445-z |
| spellingShingle | Manchao Zhang Scarlett Acklin John Gillenwater Wuying Du Mousumi Patra Hao Yu Bo Xu Jianhua Yu Fen Xia SIRT2 promotes murine melanoma progression through natural killer cell inhibition Scientific Reports |
| title | SIRT2 promotes murine melanoma progression through natural killer cell inhibition |
| title_full | SIRT2 promotes murine melanoma progression through natural killer cell inhibition |
| title_fullStr | SIRT2 promotes murine melanoma progression through natural killer cell inhibition |
| title_full_unstemmed | SIRT2 promotes murine melanoma progression through natural killer cell inhibition |
| title_short | SIRT2 promotes murine melanoma progression through natural killer cell inhibition |
| title_sort | sirt2 promotes murine melanoma progression through natural killer cell inhibition |
| url | https://doi.org/10.1038/s41598-021-92445-z |
| work_keys_str_mv | AT manchaozhang sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT scarlettacklin sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT johngillenwater sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT wuyingdu sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT mousumipatra sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT haoyu sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT boxu sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT jianhuayu sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition AT fenxia sirt2promotesmurinemelanomaprogressionthroughnaturalkillercellinhibition |