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Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN.

ABSTRACT: BACKGROUND:Diabetic patients have a higher risk factor for colorectal cancer (CRC) metastasis. Stearoyl-CoA desaturase 1 (SCD1), the main enzyme responsible for producing monounsaturated fatty acids(MUFA) from saturated fatty acids, is frequently deregulated in both diabetes and CRC. The function and mechanism of SCD1 in metastasis of CRC and its relevance to glucose remains largely unknown. METHODS:SCD1 expression levels were analyzed in human CRC tissues and the Cancer Browser database ( https://genome-cancer.ucsc.edu/ ). CRC cell lines stably transfected with SCD1 shRNAs or vector were established to investigate the role of SCD1 in modulating migration and invasion of CRC cells. A glucose concentration gradient was set to investigate regulation of SCD1 in CRC relevant to diabetic conditions. RESULTS:The clinical data analysis showed high expression of SCD1 in CRC tissues with a negative correlation with the prognosis of CRC. In vitro experiments revealed that SCD1 increased CRC progression through promoting epithelial-mesenchymal transition (EMT). Lipidomic analysis demonstrated that SCD1 increased MUFA levels and MUFA administration could rescue migration and invasion defect of CRC cells induced by SCD1 knockdown. Furthermore, SCD1-mediated progression of CRC was promoted by carbohydrate response-element binding protein (ChREBP) in response to high glucose. Mechanistically, hyperglycemia-SCD1-MUFA induced CRC cell migration and invasion by regulating PTEN. CONCLUSIONS:Our findings show that SCD1 promotes metastasis of CRC cells through MUFA production and suppressing PTEN in response to glucose, which may be a novel mechanism for diabetes-induced CRC metastasis.

SUBMITTER: Ran H

PROVIDER: S-EPMC5848567 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN.

Ran Hui H Zhu Yemin Y Deng Ruyuan R Zhang Qi Q Liu Xisheng X Feng Ming M Zhong Jie J Lin Shuhai S Tong Xuemei X Su Qing Q

Journal of experimental & clinical cancer research : CR 20180312 1

<h4>Background</h4>Diabetic patients have a higher risk factor for colorectal cancer (CRC) metastasis. Stearoyl-CoA desaturase 1 (SCD1), the main enzyme responsible for producing monounsaturated fatty acids(MUFA) from saturated fatty acids, is frequently deregulated in both diabetes and CRC. The function and mechanism of SCD1 in metastasis of CRC and its relevance to glucose remains largely unknown.<h4>Methods</h4>SCD1 expression levels were analyzed in human CRC tissues and the Cancer Browser d ...[more]

PMID: 29530061

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Project description:BackgroundCancer-associated fibroblasts (CAFs) coordinate the malignancy of cancer cells via secretory materials. Reprogrammed lipid metabolism and signaling play critical roles in cancer biology. Oleic acid (OA) serves as a source of energy under glucose-deficient conditions, but its function in cancer progression remains unclear. The present study investigated that CAFs in xenografted tumors had higher amounts of fatty acids, particularly OA, compared to normal fibroblasts, and promoted the cancer cell stemness in lung adenocarcinoma cells under glucose-deficient condition.MethodsXenografts were established in immunodeficient mice by injection of NCI-H460 (H460) cells. Lipids and fatty acids were evaluated using the BODIPY staining and fatty-acid methyl esters analysis. The expression levels of markers for lipid metabolism and cancer stemness were determined by western blot, flow cytometry, and real-time PCR. Cancer cell subclones against stearoyl-CoA desaturase (SCD) were produced by lentiviral vector and CRISPR/cas9 systems. The expression of SCD was examined immunochemically in human adenocarcinoma tissues, and its clinical relevance to survival rate in lung adenocarcinoma patients was assessed by Kaplan-Meier analysis.ResultsTransferred CAF-derived OA through lipid transporter upregulated SCD in cancer cells under glucose-deficient conditions, resulting in enhanced lipid metabolism and autophagosome maturation. By OA treatment under glucose deficient condition, cancer cell stemness was significantly enhanced through sequential activation of SCD, F-actin polymerization and nuclear translocation of yes-associated protein. These findings were confirmed by experiments using chemical inhibitors, SCD-overexpressing cells and SCD-knockout (KO) cells. When xenografted, SCD-overexpressing cells produced larger tumors compared with parental cells, while SCD-KO cells generated much smaller tumors. Analysis of tumor tissue microarray from lung adenocarcinoma patients revealed that SCD expression was the marker for poor prognosis involving tumor grade, clinical stage and survival rate.ConclusionOur data indicate that CAFs-derived OA activated lipid metabolism in lung adenocarcinoma cells under glucose-deficient conditions, subsequently enhancing stemness and progression toward malignancy.

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Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN.

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Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN.

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