Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma
Sphingolipid (SL) metabolism alterations have been frequently reported in cancer including in melanoma, a bad-prognosis skin cancer. In normal cells, de novo synthesized ceramide is mainly converted to sphingomyelin (SM), the most abundant SL, by sphingomyelin synthase 1 (SMS1) and, albeit to a less...
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2019-04-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00443/full |
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doaj-35281e352b514bb2bdc159ba35de8093 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fatima Bilal Fatima Bilal Fatima Bilal Fatima Bilal Anne Montfort Anne Montfort Anne Montfort Julia Gilhodes Virginie Garcia Virginie Garcia Joëlle Riond Joëlle Riond Stéphane Carpentier Stéphane Carpentier Stéphane Carpentier Thomas Filleron Céline Colacios Céline Colacios Céline Colacios Thierry Levade Thierry Levade Thierry Levade Thierry Levade Ahmad Daher Nicolas Meyer Nicolas Meyer Nicolas Meyer Nathalie Andrieu-Abadie Nathalie Andrieu-Abadie Bruno Ségui Bruno Ségui Bruno Ségui |
spellingShingle |
Fatima Bilal Fatima Bilal Fatima Bilal Fatima Bilal Anne Montfort Anne Montfort Anne Montfort Julia Gilhodes Virginie Garcia Virginie Garcia Joëlle Riond Joëlle Riond Stéphane Carpentier Stéphane Carpentier Stéphane Carpentier Thomas Filleron Céline Colacios Céline Colacios Céline Colacios Thierry Levade Thierry Levade Thierry Levade Thierry Levade Ahmad Daher Nicolas Meyer Nicolas Meyer Nicolas Meyer Nathalie Andrieu-Abadie Nathalie Andrieu-Abadie Bruno Ségui Bruno Ségui Bruno Ségui Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma Frontiers in Pharmacology sphingolipids ceramide glucosylceramide prognosis biomarker cancer |
author_facet |
Fatima Bilal Fatima Bilal Fatima Bilal Fatima Bilal Anne Montfort Anne Montfort Anne Montfort Julia Gilhodes Virginie Garcia Virginie Garcia Joëlle Riond Joëlle Riond Stéphane Carpentier Stéphane Carpentier Stéphane Carpentier Thomas Filleron Céline Colacios Céline Colacios Céline Colacios Thierry Levade Thierry Levade Thierry Levade Thierry Levade Ahmad Daher Nicolas Meyer Nicolas Meyer Nicolas Meyer Nathalie Andrieu-Abadie Nathalie Andrieu-Abadie Bruno Ségui Bruno Ségui Bruno Ségui |
author_sort |
Fatima Bilal |
title |
Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma |
title_short |
Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma |
title_full |
Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma |
title_fullStr |
Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma |
title_full_unstemmed |
Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma |
title_sort |
sphingomyelin synthase 1 (sms1) downregulation is associated with sphingolipid reprogramming and a worse prognosis in melanoma |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2019-04-01 |
description |
Sphingolipid (SL) metabolism alterations have been frequently reported in cancer including in melanoma, a bad-prognosis skin cancer. In normal cells, de novo synthesized ceramide is mainly converted to sphingomyelin (SM), the most abundant SL, by sphingomyelin synthase 1 (SMS1) and, albeit to a lesser extent, SMS2, encoded by the SGMS1 and SGMS2 genes, respectively. Alternatively, ceramide can be converted to glucosylceramide (GlcCer) by the GlcCer synthase (GCS), encoded by the UGCG gene. Herein, we provide evidence for the first time that SMS1 is frequently downregulated in various solid cancers, more particularly in melanoma. Accordingly, various human melanoma cells displayed a SL metabolism signature associated with (i) a robust and a low expression of UGCG and SGMS1/2, respectively, (ii) higher in situ enzyme activity of GCS than SMS, and (iii) higher intracellular levels of GlcCer than SM. SMS1 was expressed at low levels in most of the human melanoma biopsies. In addition, several mutations and increased CpG island methylation in the SGMS1 gene were identified that likely affect SMS1 expression. Finally, low SMS1 expression was associated with a worse prognosis in metastatic melanoma patients. Collectively, our study indicates that SMS1 downregulation in melanoma enhances GlcCer synthesis, triggering an imbalance in the SM/GlcCer homeostasis, which likely contributes to melanoma progression. Evaluating SMS1 expression level in tumor samples might serve as a biomarker to predict clinical outcome in advanced melanoma patients. |
topic |
sphingolipids ceramide glucosylceramide prognosis biomarker cancer |
url |
https://www.frontiersin.org/article/10.3389/fphar.2019.00443/full |
work_keys_str_mv |
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doaj-35281e352b514bb2bdc159ba35de80932020-11-24T22:43:28ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-04-011010.3389/fphar.2019.00443437586Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in MelanomaFatima Bilal0Fatima Bilal1Fatima Bilal2Fatima Bilal3Anne Montfort4Anne Montfort5Anne Montfort6Julia Gilhodes7Virginie Garcia8Virginie Garcia9Joëlle Riond10Joëlle Riond11Stéphane Carpentier12Stéphane Carpentier13Stéphane Carpentier14Thomas Filleron15Céline Colacios16Céline Colacios17Céline Colacios18Thierry Levade19Thierry Levade20Thierry Levade21Thierry Levade22Ahmad Daher23Nicolas Meyer24Nicolas Meyer25Nicolas Meyer26Nathalie Andrieu-Abadie27Nathalie Andrieu-Abadie28Bruno Ségui29Bruno Ségui30Bruno Ségui31INSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceEcole Doctorale de Sciences et Technologies, Université Libanaise, Beirut, LebanonUniversité Toulouse III – Paul Sabatier, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceUniversité Toulouse III – Paul Sabatier, Toulouse, FranceInstitut Universitaire du Cancer, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceUniversité Toulouse III – Paul Sabatier, Toulouse, FranceInstitut Universitaire du Cancer, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceUniversité Toulouse III – Paul Sabatier, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceUniversité Toulouse III – Paul Sabatier, Toulouse, FranceLaboratoire de Biochimie, CHU Purpan, Institut Fédératif de Biologie, Toulouse, FranceEcole Doctorale de Sciences et Technologies, Université Libanaise, Beirut, LebanonINSERM UMR 1037, CRCT, Toulouse, FranceUniversité Toulouse III – Paul Sabatier, Toulouse, FranceInstitut Universitaire du Cancer, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceINSERM UMR 1037, CRCT, Toulouse, FranceEquipe Labellisée Ligue Contre Le Cancer, Toulouse, FranceUniversité Toulouse III – Paul Sabatier, Toulouse, FranceSphingolipid (SL) metabolism alterations have been frequently reported in cancer including in melanoma, a bad-prognosis skin cancer. In normal cells, de novo synthesized ceramide is mainly converted to sphingomyelin (SM), the most abundant SL, by sphingomyelin synthase 1 (SMS1) and, albeit to a lesser extent, SMS2, encoded by the SGMS1 and SGMS2 genes, respectively. Alternatively, ceramide can be converted to glucosylceramide (GlcCer) by the GlcCer synthase (GCS), encoded by the UGCG gene. Herein, we provide evidence for the first time that SMS1 is frequently downregulated in various solid cancers, more particularly in melanoma. Accordingly, various human melanoma cells displayed a SL metabolism signature associated with (i) a robust and a low expression of UGCG and SGMS1/2, respectively, (ii) higher in situ enzyme activity of GCS than SMS, and (iii) higher intracellular levels of GlcCer than SM. SMS1 was expressed at low levels in most of the human melanoma biopsies. In addition, several mutations and increased CpG island methylation in the SGMS1 gene were identified that likely affect SMS1 expression. Finally, low SMS1 expression was associated with a worse prognosis in metastatic melanoma patients. Collectively, our study indicates that SMS1 downregulation in melanoma enhances GlcCer synthesis, triggering an imbalance in the SM/GlcCer homeostasis, which likely contributes to melanoma progression. Evaluating SMS1 expression level in tumor samples might serve as a biomarker to predict clinical outcome in advanced melanoma patients.https://www.frontiersin.org/article/10.3389/fphar.2019.00443/fullsphingolipidsceramideglucosylceramideprognosis biomarkercancer |