SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle
Abstract MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, lea...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-10-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301871 |
| _version_ | 1797663905240055808 |
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| author | Xiaowei She Qi Wu Zejun Rao Da Song Changsheng Huang Shengjie Feng Anyi Liu Lang Liu Kairui Wan Xun Li Chengxin Yu Cheng Qiu Xuelai Luo Junbo Hu Guihua Wang Feng Xu Li Sun |
| author_facet | Xiaowei She Qi Wu Zejun Rao Da Song Changsheng Huang Shengjie Feng Anyi Liu Lang Liu Kairui Wan Xun Li Chengxin Yu Cheng Qiu Xuelai Luo Junbo Hu Guihua Wang Feng Xu Li Sun |
| author_sort | Xiaowei She |
| collection | DOAJ |
| description | Abstract MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post‐translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip‐mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri‐methylation promotes tumor glycolysis and M2‐like polarization of tumor‐associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri‐methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC. |
| first_indexed | 2024-03-11T19:22:31Z |
| format | Article |
| id | doaj.art-dc07c14d17494bbab0d30599c1fb7309 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T19:22:31Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-dc07c14d17494bbab0d30599c1fb73092023-10-07T03:51:49ZengWileyAdvanced Science2198-38442023-10-011028n/an/a10.1002/advs.202301871SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate ShuttleXiaowei She0Qi Wu1Zejun Rao2Da Song3Changsheng Huang4Shengjie Feng5Anyi Liu6Lang Liu7Kairui Wan8Xun Li9Chengxin Yu10Cheng Qiu11Xuelai Luo12Junbo Hu13Guihua Wang14Feng Xu15Li Sun16GI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaGI Cancer Research Institute Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaDepartment of Oncology Tongji Hospital Huazhong University of Science and Technology Wuhan 430030 P. R. ChinaAbstract MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post‐translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip‐mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri‐methylation promotes tumor glycolysis and M2‐like polarization of tumor‐associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri‐methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.https://doi.org/10.1002/advs.202301871lactate shuttleMCT1 methylationSETDB1tumor progression |
| spellingShingle | Xiaowei She Qi Wu Zejun Rao Da Song Changsheng Huang Shengjie Feng Anyi Liu Lang Liu Kairui Wan Xun Li Chengxin Yu Cheng Qiu Xuelai Luo Junbo Hu Guihua Wang Feng Xu Li Sun SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle Advanced Science lactate shuttle MCT1 methylation SETDB1 tumor progression |
| title | SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle |
| title_full | SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle |
| title_fullStr | SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle |
| title_full_unstemmed | SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle |
| title_short | SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle |
| title_sort | setdb1 methylates mct1 promoting tumor progression by enhancing the lactate shuttle |
| topic | lactate shuttle MCT1 methylation SETDB1 tumor progression |
| url | https://doi.org/10.1002/advs.202301871 |
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