ECHS1, an interacting protein of LASP1, induces sphingolipid-metabolism imbalance to promote colorectal cancer progression by regulating ceramide glycosylation.
ECHS1, an interacting protein of LASP1, induces sphingolipid-metabolism imbalance to promote colorectal cancer progression by regulating ceramide glycosylation.
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ECHS1 是 LASP1 的相互作用蛋白，通过调节神经酰胺糖基化诱导鞘脂代谢失衡，促进结直肠癌进展
DOI：
10.1038/s41419-021-04213-6
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发表时间：
2021-10-06
影响因子：
9
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Li R;Hao Y;Wang Q;Meng Y;Wu K;Liu C;Xu L;Liu Z;Zhao L
鞘磷脂代谢紊乱越来越被认为是多种肿瘤的耐药机制。本研究通过LC-MS鉴定LIM和SH3蛋白1(LASP1)是鞘磷脂代谢相关蛋白，通过蛋白质分析鉴定短链Enoyl-CoA水合酶(ECHS1)是结直肠癌(CRC)中LASP1相互作用的新蛋白。功能获得和功能丧失分析表明，ECHS1在体外和体内对结直肠癌细胞的增殖、迁移和侵袭起刺激作用。对支持肿瘤的肿瘤代谢的机制研究表明，ECHS1能够通过促进UDP-葡萄糖神经酰胺糖基转移酶(UGCG)来改变神经酰胺(Cer)代谢，从而增加神经鞘糖脂的合成(HexCer)。进一步分析表明，ECHS1通过PI3K/Akt/mTOR依赖的信号通路释放活性氧物种(ROS)，干扰线粒体膜电位，从而促进大肠癌的进展和耐药。同时，UCCG的特异性抑制剂Eliglustat在体内外均能逆转ECHS1诱导的大肠癌细胞存活和耐药现象。免疫组化检测显示ECHS1在结直肠癌组织中高表达，与结直肠癌的分化程度及预后不良有关。这项研究为磷脂促进结直肠癌耐药的机制提供了新的见解，并确定了未来治疗的潜在靶点。
Sphingolipid metabolic dysregulation has increasingly been considered to be a drug-resistance mechanism for a variety of tumors. In this study, through an LC–MS assay, LIM and SH3 protein 1 (LASP1) was identified as a sphingolipid-metabolism-involved protein, and short-chain enoyl-CoA hydratase (ECHS1) was identified as a new LASP1-interacting protein through a protein assay in colorectal cancer (CRC). Gain- and loss-of-function analyses demonstrated the stimulatory role played by ECHS1 in CRC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistic studies of the underlying tumor-supportive oncometabolism indicate that ECHS1 enables altering ceramide (Cer) metabolism that increases glycosphingolipid synthesis (HexCer) by promoting UDP-glucose ceramide glycosyltransferase (UGCG). Further analysis showed that ECHS1 promotes CRC progression and drug resistance by releasing reactive oxygen species (ROS) and interfering mitochondrial membrane potential via the PI3K/Akt/mTOR-dependent signaling pathway. Meanwhile, the phenomenon of promoting the survival and drug resistance of CRC cells caused by ECHS1 could be reversed by Eliglustat, a specific inhibitor of UCCG, in vitro and in vivo. IHC assay showed that ECHS1 was overexpressed in CRC tissues, which was related to the differentiation and poor prognosis of CRC patients. This study provides new insight into the mechanism by which phospholipids promote drug resistance in CRC and identifies potential targets for future therapies.
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