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Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin.

ABSTRACT: Breast cancer is the most common type of carcinoma in women worldwide, but the mechanisms underlying tumour development and progression remain unclear. Sphingomyelin synthase 2 (SGMS2) is a crucial regulator involved in ceramide (Cer) and sphingomyelin (SM) homoeostasis that is mostly studied for its role in lipid metabolism. Our primary study indicated that high SGMS2 expression is associated with breast cancer metastasis. Gain- and loss-of-function assays in vitro and in vivo revealed that SGMS2 promotes cancer cell proliferation by suppressing apoptosis through a Cer-associated pathway and promotes cancer cell invasiveness by enhancing epithelial-to-mesenchymal transition (EMT) initiation through the TGF-?/Smad signalling pathway. Further study determined that SGMS2 activated the TGF-?/Smad signalling pathway primarily by increasing TGF-?1 secretion, which was likely associated with aberrant expression of SM. Thus, our findings indicate that SGMS2-mediated activation of the TGF-?/Smad signalling pathway is important in breast cancer progression, which provides new insight into the mechanisms underlying breast cancer metastasis and suggests a possible anticancer therapy for breast cancer.

SUBMITTER: Zheng K

PROVIDER: S-EPMC6377618 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin.

Zheng Kehong K Chen Zetao Z Feng Haizhan H Chen Ying Y Zhang Cheng C Yu Jinlong J Luo Yunfeng Y Zhao Liang L Jiang Xiancheng X Shi Fujun F

Cell death & disease 20190215 3

Breast cancer is the most common type of carcinoma in women worldwide, but the mechanisms underlying tumour development and progression remain unclear. Sphingomyelin synthase 2 (SGMS2) is a crucial regulator involved in ceramide (Cer) and sphingomyelin (SM) homoeostasis that is mostly studied for its role in lipid metabolism. Our primary study indicated that high SGMS2 expression is associated with breast cancer metastasis. Gain- and loss-of-function assays in vitro and in vivo revealed that SGM ...[more]

PMID: 30770781

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Project description:BackgroundCeramide, a bioactive signaling sphingolipid, has long been implicated in cancer. Members of the ceramide synthase (CerS) family determine the acyl chain lengths of ceramides, with ceramide synthase 4 (CerS4) primarily generating C18-C20-ceramide. Although CerS4 is known to be overexpressed in breast cancer, its role in breast cancer pathogenesis is not well established.MethodsTo investigate the role of CerS4 in breast cancer, public datasets, including The Cancer Genome Atlas (TCGA) and two Gene Expression Omnibus (GEO) datasets (GSE115577 and GSE96058) were analyzed. Furthermore, MCF-7 cells stably overexpressing CerS4 (MCF-7/CerS4) as a model for luminal subtype A (LumA) breast cancer were produced, and doxorubicin (also known as Adriamycin [AD])-resistant MCF-7/ADR cells were generated after prolonged treatment of MCF-7 cells with doxorubicin. Kaplan-Meier survival analysis assessed the clinical significance of CERS4 expression, while Student's t-tests or Analysis of Variance (ANOVA) compared gene expression and cell viability in different MCF-7 cell lines.ResultsAnalysis of the public datasets revealed elevated CERS4 expression in breast cancer, especially in the most common breast cancer subtype, LumA. Persistent CerS4 overexpression in MCF-7 cells activated multiple cancer-associated pathways, including pathways involving sterol regulatory element-binding protein, nuclear factor kappa B (NF-κB), Akt/mammalian target of rapamycin (mTOR), and β-catenin. Furthermore, MCF-7/CerS4 cells acquired doxorubicin, paclitaxel, and tamoxifen resistance, with concomitant upregulation of ATP-binding cassette (ABC) transporter genes, such as ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2. MCF-7/CerS4 cells were characterized by increased cell migration and epithelial-mesenchymal transition (EMT). Finally, CERS4 knockdown in doxorubicin-resistant MCF-7/ADR cells resulted in reduced activation of cancer-associated pathways (NF-κB, Akt/mTOR, β-catenin, and EMT) and diminished chemoresistance, accompanied by ABCB1 and ABCC1 downregulation.ConclusionsChronic CerS4 overexpression may exert oncogenic effects in breast cancer via alterations in signaling, EMT, and chemoresistance. Therefore, CerS4 may represent an attractive target for anticancer therapy, especially in LumA breast cancer.

Dataset Information

Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin.

Publications

Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin.

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