Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer
Abstract Background Branched-chain amino acid (BCAA) metabolism is dysregulated in colorectal cancer (CRC), with elevated plasma BCAA levels significantly associated with an increased risk of developing the disease. However, whether BCAAs directly promote CRC progression and their underlying mechani...
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BMC
2025-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03399-3 |
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| author | Zhenkang Li Zhengyu Liu Mingdao Lin Huayang Pan Yuechen Liu Yang Liu Yuwen Xie Jinchao Zhang Shenyuan Guan Yongsheng Li Mulan Zhu Yuan Fang Zhiyong Shen Haijun Deng |
| author_facet | Zhenkang Li Zhengyu Liu Mingdao Lin Huayang Pan Yuechen Liu Yang Liu Yuwen Xie Jinchao Zhang Shenyuan Guan Yongsheng Li Mulan Zhu Yuan Fang Zhiyong Shen Haijun Deng |
| author_sort | Zhenkang Li |
| collection | DOAJ |
| description | Abstract Background Branched-chain amino acid (BCAA) metabolism is dysregulated in colorectal cancer (CRC), with elevated plasma BCAA levels significantly associated with an increased risk of developing the disease. However, whether BCAAs directly promote CRC progression and their underlying mechanisms remain unclear. Methods In this study, we investigated the metabolic alterations in KRAS-mutant CRC. We examined the effects of restricting BCAA supply on the proliferation and metastasis of KRAS-mutant CRC cells both in vitro and in vivo. Results We found that in KRAS-mutant CRC, BCAAs and their metabolic products accumulate markedly. Restricting the BCAA supply specifically inhibits the proliferation of KRAS-mutant CRC cells but does not affect metastasis. In these cancer cells, enoyl-CoA hydratase-1 (ECHS1), a key enzyme in BCAA metabolism, is downregulated. Furthermore, BCAAs enhance the acetylation of lysine 204 on ECHS1, impairing its ability to bind enoyl-CoA and reducing its catalytic activity. This modification triggers the ubiquitination of ECHS1 and its subsequent degradation, diminishing BCAA catabolism and leading to its cellular accumulation. This accumulation activates the mTORC1 signaling pathway, which induces the transcriptional activation of downstream target proteins and promotes the malignant progression of CRC. Conclusions Limiting BCAA intake not only suppresses tumor growth in KRAS-mutant CRC but also enhances the efficacy of the KRAS G12D inhibitor MRTX1133 and the monoclonal antibody bevacizumab. Our findings reveal a previously unknown regulatory mechanism of ECHS1 in CRC and offer new potential therapeutic targets. |
| format | Article |
| id | doaj-art-778cb75b7281478891df2eae7434de28 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-778cb75b7281478891df2eae7434de282025-08-20T02:07:41ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-05-0144111910.1186/s13046-025-03399-3Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancerZhenkang Li0Zhengyu Liu1Mingdao Lin2Huayang Pan3Yuechen Liu4Yang Liu5Yuwen Xie6Jinchao Zhang7Shenyuan Guan8Yongsheng Li9Mulan Zhu10Yuan Fang11Zhiyong Shen12Haijun Deng13Department of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Anorectal Surgery, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical UniversityDepartment of Radiation Oncology, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, Southern Medical UniversityAbstract Background Branched-chain amino acid (BCAA) metabolism is dysregulated in colorectal cancer (CRC), with elevated plasma BCAA levels significantly associated with an increased risk of developing the disease. However, whether BCAAs directly promote CRC progression and their underlying mechanisms remain unclear. Methods In this study, we investigated the metabolic alterations in KRAS-mutant CRC. We examined the effects of restricting BCAA supply on the proliferation and metastasis of KRAS-mutant CRC cells both in vitro and in vivo. Results We found that in KRAS-mutant CRC, BCAAs and their metabolic products accumulate markedly. Restricting the BCAA supply specifically inhibits the proliferation of KRAS-mutant CRC cells but does not affect metastasis. In these cancer cells, enoyl-CoA hydratase-1 (ECHS1), a key enzyme in BCAA metabolism, is downregulated. Furthermore, BCAAs enhance the acetylation of lysine 204 on ECHS1, impairing its ability to bind enoyl-CoA and reducing its catalytic activity. This modification triggers the ubiquitination of ECHS1 and its subsequent degradation, diminishing BCAA catabolism and leading to its cellular accumulation. This accumulation activates the mTORC1 signaling pathway, which induces the transcriptional activation of downstream target proteins and promotes the malignant progression of CRC. Conclusions Limiting BCAA intake not only suppresses tumor growth in KRAS-mutant CRC but also enhances the efficacy of the KRAS G12D inhibitor MRTX1133 and the monoclonal antibody bevacizumab. Our findings reveal a previously unknown regulatory mechanism of ECHS1 in CRC and offer new potential therapeutic targets.https://doi.org/10.1186/s13046-025-03399-3Colorectal cancerKRASBCAAsAcetylation |
| spellingShingle | Zhenkang Li Zhengyu Liu Mingdao Lin Huayang Pan Yuechen Liu Yang Liu Yuwen Xie Jinchao Zhang Shenyuan Guan Yongsheng Li Mulan Zhu Yuan Fang Zhiyong Shen Haijun Deng Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer Journal of Experimental & Clinical Cancer Research Colorectal cancer KRAS BCAAs Acetylation |
| title | Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer |
| title_full | Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer |
| title_fullStr | Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer |
| title_full_unstemmed | Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer |
| title_short | Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer |
| title_sort | acetylation induced degradation of echs1 enhances bcaa accumulation and proliferation in kras mutant colorectal cancer |
| topic | Colorectal cancer KRAS BCAAs Acetylation |
| url | https://doi.org/10.1186/s13046-025-03399-3 |
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