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

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.

Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

“…On one hand, this interaction induces cell apoptosis by decreasing the mitochondrial membrane potential and reduces the phosphorylation of a serine/threonine protein kinase (Akt). On the other hand, it leads to an increased reactive oxygen species (ROS) production and promotes UDP-glucose ceramide glycosyltransferase which contributes to the alteration of ceramide metabolism[ 24 ]. Furthermore, HBsAg can inhibit jumping translocation breakpoints leading to increased cell motility and decreased apoptosis[ 13 ].…”

Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection

“…Enoyl-CoA hydratase 1 (ECHS1) is an enzyme that promotes the glycosylation of ceramide, which is believed to be a key step in chemotherapy resistance. Monitoring this marker may assist in the selection of appropriate patients for chemotherapy [133]. Another marker, N-MYC downstream-regulated gene 1 (NDRG1), a key regulator of a variety of cell growth regulatory processes and signaling pathways, was shown to enhance chemosensitivity by modulating EGFR trafficking in metastatic CRC [134].…”

Biological Role and Mechanism of Lipid Metabolism Reprogramming Related Gene ECHS1 in Cancer

“… 63 Li et al found by immunoprecipitation assay that highly expressed ECHS1 binds to the tumor-promoting factor LIM and SH3 protein 1, increasing the glycosylation of ceramide, reprogramming sphingolipid metabolism, thus reducing ceramide levels and inducing drug resistance in colorectal cancer (CRC) cells. 55 In summary, ECHS1-mediated reprogramming of lipid metabolism is mainly reflected in both remodeling of fatty acid and sphingolipid metabolism, and the regulation of fatty acid metabolism reprogramming by ECHS1 may have cancer species specificity.…”

“…Li et al found that endogenous overexpression of ECHS1 significantly enhances the metastatic and invasive ability of HCT116 cells. 55 In addition, it has been found in cancers with high expression of ECHS1, such as ovarian cancer, 42 , 75 breast cancer, 38 , 76 and colon cancer, 37 , 77 that cancer cells tend to spread to adipocyte-rich tissues. Which probably since lipids stored in adipocytes can derive large amounts of fatty acids that generate ATP via FAO to facilitate rapid growth and metastasis of cancer cells.…”

“…In response to internal stimuli such as irreparable genetic damage, hypoxia, extremely high cytoplasmic Ca 2+ concentrations, and severe oxidative stress, the mitochondrial outer membrane permeabilization (MOMP) is altered, resulting in the release of multiple pro-apoptotic factors from the inner and outer mitochondrial membrane gaps into the cytoplasm, such as cytochrome C, apoptosis-inducing factor, and EndoG, thereby activating caspase-9 to trigger apoptosis. 89 It was found that knockdown of ECHS1 in SW480 cells promotes mitochondrial reactive oxygen species production and decreased mitochondrial membrane potential (MMP) to induce apoptosis by inhibiting ceramide glycosylation 55 which promotes apoptosis by affecting Bax integration through ceramide-rich macro-domains on the mitochondrial membrane 90 , 91 and inducing MOMP. 92 Therefore, mitochondria may be a key organelle in the regulation of apoptosis by ECHS1 through metabolic pathways.…”