Regulation of CerS4 un human colon cells and its role in colon carcinogenesis
Final Report Abstract
Sphingolipids are components of cell membranes and play an important role in cell communication as signaling molecules. Central enzymes of the sphingolipid de novo synthesis are six different ceramide synthases (CerS) 1-6, which have different substrate specificities and are differentially expressed in various tissues. In intestinal tissues, CerS2,4,5,6 are mainly expressed, whereas CerS1 and CerS3 are negligible expressed. We have found that the expression of CerS4 is greatly reduced in human colon tumors compared to control tissues. In this project, we explored the molecular mechanisms that lead to the suppression of CerS4 expression in colon epithelial cells and how this impacts colon carcinogenesis. Our results show that CerS4 expression in colon epithelial cells can be downregulated by both hypoxia and histone deacetylases (HDAC). In this context, regulation of CerS4 occurs at the promoter and mRNA (3`-UTR) levels. Hypoxia occurs in insufficiently vascularized areas of solid tumors, and histone deacetylases are frequently overexpressed in tumors. Both phenomena are associated with tumor-promoting mechanisms. We further demonstrated that decreased expression of CerS4 in undifferentiated colon tumor cells corresponding to late tumor stage UICC IV, has a proliferation-promoting effect and is associated with metabolic changes in the cell. Due to an enhanced expression of cellular transport proteins the cells take up more glucose, glutamine and fatty acids. Glucose, glutamine or fatty acids are metabolized via the pentose phosphate pathway to precursors of nucleotides or are used for energy production. In contrast, studies in mice and also in human colon tumor cells, that are similar to an early tumor stage, showed that downregulation of CerS4 in the early phase of carcinogenesis rather has a protective effect. Our investigations revealed out CerS4 expression as a biomarker in late colon tumor stages which is associated with poor prognosis for patients. The metabolic changes in these cells, induced by a decreased CerS4 expression, may represent new treatment options for a personalized tumor therapy.
Publications
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How sphingolipids affect T cells in the resolution of inflammation. Frontiers in Pharmacology, 13.
Hartel, Jennifer Christina; Merz, Nadine & Grösch, Sabine
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T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model. International Journal of Molecular Sciences, 23(3), 1866.
El-Hindi, Khadija; Brachtendorf, Sebastian; Hartel, Jennifer Christina; Oertel, Stephanie; Birod, Kerstin; Merz, Nadine; Trautmann, Sandra; Thomas, Dominique; Weigert, Andreas; Schäufele, Tim J.; Scholich, Klaus; Schiffmann, Susanne; Ulshöfer, Thomas; Utermöhlen, Olaf & Grösch, Sabine
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Hypoxia induced deregulation of sphingolipids in colon cancer is a prognostic marker for patient outcome. Biochimica et Biophysica Acta (BBA) -Molecular Basis of Disease, 1870(1), 166906.
El Hindi, Khadija; Brachtendorf, Sebastian; Hartel, Jennifer C.; Renné, Christoph; Birod, Kerstin; Schilling, Karin; Labocha, Sandra; Thomas, Dominique; Ferreirós, Nerea; Hahnefeld, Lisa; Dorochow, Erika; Del Turco, Domenico; Deller, Thomas; Scholich, Klaus; Fuhrmann, Dominik C.; Weigert, Andreas; Brüne, Bernhard; Geisslinger, Gerd; Wittig, Ilka ... & Grösch, Sabine
