Li Zhenkang, Liu Zhengyu, Lin Mingdao, Pan Huayang, Liu Yuechen, Liu Yang, Xie Yuwen, Zhang Jinchao, Guan Shenyuan, Li Yongsheng, Zhu Mulan, Fang Yuan, Shen Zhiyong, Deng Haijun
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
Department of Anorectal Surgery, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University, Haikou, Hainan Province, 570311, China.
J Exp Clin Cancer Res. 2025 May 28;44(1):164. doi: 10.1186/s13046-025-03399-3.
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.
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.
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.
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.
支链氨基酸（BCAA）代谢在结直肠癌（CRC）中失调，血浆BCAA水平升高与患该疾病风险增加显著相关。然而，BCAAs是否直接促进CRC进展及其潜在机制仍不清楚。
在本研究中，我们调查了KRAS突变型CRC中的代谢改变。我们在体外和体内研究了限制BCAA供应对KRAS突变型CRC细胞增殖和转移的影响。
我们发现，在KRAS突变型CRC中，BCAAs及其代谢产物显著积累。限制BCAA供应特异性抑制KRAS突变型CRC细胞的增殖，但不影响转移。在这些癌细胞中，BCAA代谢的关键酶烯酰辅酶A水合酶-1（ECHS1）下调。此外，BCAAs增强了ECHS1上赖氨酸204的乙酰化，损害其与烯酰辅酶A结合的能力并降低其催化活性。这种修饰触发ECHS1的泛素化及其随后的降解，减少BCAA分解代谢并导致其在细胞内积累。这种积累激活mTORC1信号通路，诱导下游靶蛋白的转录激活并促进CRC的恶性进展。
限制BCAA摄入不仅抑制KRAS突变型CRC中的肿瘤生长，还增强KRAS G12D抑制剂MRTX1133和单克隆抗体贝伐单抗的疗效。我们的发现揭示了ECHS1在CRC中以前未知的调节机制，并提供了新的潜在治疗靶点。
