RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32
Melanoma is a dangerous form of skin cancer, making it important to investigate new mechanisms and approaches to enhance the effectiveness of treatment. Here, we establish a positive correlation between the human rhomboid family-1 (RHBDF1) protein and melanoma malignancy. We demonstrate that the mel...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823003511 |
| _version_ | 1827609665902477312 |
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| author | Lei Wang Yuan-Yuan Song Yan Wang Xiu-Xiu Liu Yi-Lun Yin Shan Gao Fan Zhang Lu-Yuan Li Zhi-Song Zhang |
| author_facet | Lei Wang Yuan-Yuan Song Yan Wang Xiu-Xiu Liu Yi-Lun Yin Shan Gao Fan Zhang Lu-Yuan Li Zhi-Song Zhang |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | Melanoma is a dangerous form of skin cancer, making it important to investigate new mechanisms and approaches to enhance the effectiveness of treatment. Here, we establish a positive correlation between the human rhomboid family-1 (RHBDF1) protein and melanoma malignancy. We demonstrate that the melanoma RHBDF1 decrease dramatically inhibits tumor growth and the development of lung metastases, which may be related to the impaired glycolysis. We show that RHBDF1 function is essential to the maintenance of high levels of glycolytic enzymes, especially glucose-6-phosphate isomerase (GPI). Additionally, we discover that the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) mediates the K27/K63-linked ubiquitination of GPI and the ensuing lysosomal degradation process. We prove that the multi-transmembrane domain of RHBDF1 is in competition with GPI, preventing the latter from interacting with NCL1-HT2A-LIN41 (NHL) domain of TRIM32. We also note that the mouse RHBDF1's R747 and Y799 are crucial for competitive binding and GPI protection. Artificially silencing the Rhbdf1 gene in a mouse melanoma model results in declined lactic acid levels, elevated cytotoxic lymphocyte infiltration, and improved tumor responsiveness to immunotherapy. These results provide credence to the hypothesis that RHBDF1 plays a significant role in melanoma regulation and suggest that blocking RHBDF1 may be an efficient technique for reestablishing the tumor immune microenvironment (TIME) in melanoma and halting its progression. |
| first_indexed | 2024-03-09T07:36:43Z |
| format | Article |
| id | doaj.art-e1059d0f1b0348dda784a44fea6ddc3d |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T07:36:43Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-e1059d0f1b0348dda784a44fea6ddc3d2023-12-03T05:39:40ZengElsevierPharmacological Research1096-11862023-12-01198106995RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32Lei Wang0Yuan-Yuan Song1Yan Wang2Xiu-Xiu Liu3Yi-Lun Yin4Shan Gao5Fan Zhang6Lu-Yuan Li7Zhi-Song Zhang8State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Center for Brain Science and Disease, Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang 050017, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, ChinaThe Key Laboratory of Neural and Vascular Biology, Ministry of Education, Center for Brain Science and Disease, Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang 050017, ChinaState Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; Correspondence to: State Key Laboratory of Medicinal Chemical Biology, Nankai University, 38 Tongyan Road, Jinnan District, 300350 Tianjin, China.State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, the Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; Correspondence to: College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, 300350 Tianjin, China.Melanoma is a dangerous form of skin cancer, making it important to investigate new mechanisms and approaches to enhance the effectiveness of treatment. Here, we establish a positive correlation between the human rhomboid family-1 (RHBDF1) protein and melanoma malignancy. We demonstrate that the melanoma RHBDF1 decrease dramatically inhibits tumor growth and the development of lung metastases, which may be related to the impaired glycolysis. We show that RHBDF1 function is essential to the maintenance of high levels of glycolytic enzymes, especially glucose-6-phosphate isomerase (GPI). Additionally, we discover that the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) mediates the K27/K63-linked ubiquitination of GPI and the ensuing lysosomal degradation process. We prove that the multi-transmembrane domain of RHBDF1 is in competition with GPI, preventing the latter from interacting with NCL1-HT2A-LIN41 (NHL) domain of TRIM32. We also note that the mouse RHBDF1's R747 and Y799 are crucial for competitive binding and GPI protection. Artificially silencing the Rhbdf1 gene in a mouse melanoma model results in declined lactic acid levels, elevated cytotoxic lymphocyte infiltration, and improved tumor responsiveness to immunotherapy. These results provide credence to the hypothesis that RHBDF1 plays a significant role in melanoma regulation and suggest that blocking RHBDF1 may be an efficient technique for reestablishing the tumor immune microenvironment (TIME) in melanoma and halting its progression.http://www.sciencedirect.com/science/article/pii/S1043661823003511MelanomaImmunotherapyGlycolysisRHBDF1GPI |
| spellingShingle | Lei Wang Yuan-Yuan Song Yan Wang Xiu-Xiu Liu Yi-Lun Yin Shan Gao Fan Zhang Lu-Yuan Li Zhi-Song Zhang RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32 Pharmacological Research Melanoma Immunotherapy Glycolysis RHBDF1 GPI |
| title | RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32 |
| title_full | RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32 |
| title_fullStr | RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32 |
| title_full_unstemmed | RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32 |
| title_short | RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32 |
| title_sort | rhbdf1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose 6 phosphate isomerase degradation via trim32 |
| topic | Melanoma Immunotherapy Glycolysis RHBDF1 GPI |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823003511 |
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