ECHS1, an interacting protein of LASP1, induces sphingolipid-metabolism imbalance to promote colorectal cancer progression by regulating ceramide glycosylation

Rui Li,Rui Li,Yanyu Hao,Qiuhan Wang,Liang Zhao,Liang Zhao,Kunhe Wu,Ziguang Liu,Ziguang Liu,Yuan Meng,Lijun Xu,Chaoqun Liu

doi:10.1038/s41419-021-04213-6

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.

Highlights

Colorectal cancer (CRC) is one of the most common malignant tumors threatening human health worldwide [1]
On the basis of our previous study, we found that LIM and SH3 protein 1 (LASP1) was highly overexpressed in CRC tissues which is positively associated with lymph node and distant metastasis [7]
By using comparative proteomics methods to identify LASP1-related proteins involved in regulating tumor progression, a series of proteins related to cytoskeleton [8], epithelial–mesenchymal transition (EMT), and metabolism is found to interact with LASP1 to promote aggressive phenotype of CRC cells

Summary

Introduction

Colorectal cancer (CRC) is one of the most common malignant tumors threatening human health worldwide [1]. Despite significant progress in chemotherapy, inherent or acquired chemoresistance, especially multidrug resistance (MDR), is the main obstacle to this development, leading to inefficient cancer-cell killing and subsequent patient relapse [2]. It is essential to understand the biological mechanisms underlying MDR more comprehensively to benefit patients with CRC or other tumors. By using comparative proteomics methods to identify LASP1-related proteins involved in regulating tumor progression, a series of proteins related to cytoskeleton [8], epithelial–mesenchymal transition (EMT), and metabolism is found to interact with LASP1 to promote aggressive phenotype of CRC cells. There have been many researches on the molecular mechanism of LASP1 promoting the progression of CRC, it promotes cell metabolism, especially regarding sphingolipid metabolism, which has not been elucidated in detail. The molecular mechanism underlying this interaction, especially regarding sphingolipid metabolism, has not been elucidated in detail

Results

Discussion

Conclusion