1. Academic Validation
  2. 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

  • Cell Death Dis. 2021 Oct 6;12(10):911. doi: 10.1038/s41419-021-04213-6.
Rui Li 1 2 Yanyu Hao 2 Qiuhan Wang 2 Yuan Meng 3 Kunhe Wu 4 Chaoqun Liu 2 Lijun Xu 2 Ziguang Liu 1 Liang Zhao 5 6
Affiliations

Affiliations

  • 1 Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
  • 2 Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 3 Department of Pathology, The Second People's Hospital of Longgang District, Shenzhen, China.
  • 4 Department of Pathology, Guangdong Women and Children Hospital, Guangzhou, Guangdong, 511442, China.
  • 5 Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. liangsmu@foxmail.com.
  • 6 Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. liangsmu@foxmail.com.
Abstract

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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