Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOP4GV1)

DOT Name Ceramide synthase 6 (CERS6)
Synonyms CerS6; LAG1 longevity assurance homolog 6; Sphingoid base N-palmitoyltransferase CERS6; EC 2.3.1.291
Gene Name CERS6
Related Disease
Invasive breast carcinoma ( )
Acute lymphocytic leukaemia ( )
Advanced cancer ( )
Alcoholic liver diseases ( )
Childhood acute lymphoblastic leukemia ( )
Colorectal carcinoma ( )
Drug dependence ( )
Fatty liver disease ( )
Head-neck squamous cell carcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Metabolic disorder ( )
Mitochondrial disease ( )
Multiple sclerosis ( )
Neoplasm ( )
Nervous system inflammation ( )
Non-insulin dependent diabetes ( )
Non-small-cell lung cancer ( )
Substance abuse ( )
Substance dependence ( )
T-cell acute lymphoblastic leukaemia ( )
Breast cancer ( )
Breast carcinoma ( )
Graft-versus-host disease ( )
Kennedy disease ( )
Colitis ( )
Gastric cancer ( )
Melanoma ( )
Obesity ( )
Squamous cell carcinoma ( )
Stomach cancer ( )
UniProt ID
CERS6_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
2.3.1.291
Pfam ID
PF00046 ; PF03798
Sequence
MAGILAWFWNERFWLPHNVTWADLKNTEEATFPQAEDLYLAFPLAFCIFMVRLIFERFVA
KPCAIALNIQANGPQIAPPNAILEKVFTAITKHPDEKRLEGLSKQLDWDVRSIQRWFRQR
RNQEKPSTLTRFCESMWRFSFYLYVFTYGVRFLKKTPWLWNTRHCWYNYPYQPLTTDLHY
YYILELSFYWSLMFSQFTDIKRKDFGIMFLHHLVSIFLITFSYVNNMARVGTLVLCLHDS
ADALLEAAKMANYAKFQKMCDLLFVMFAVVFITTRLGIFPLWVLNTTLFESWEIVGPYPS
WWVFNLLLLLVQGLNCFWSYLIVKIACKAVSRGKVSKDDRSDIESSSDEEDSEPPGKNPH
TATTTNGTSGTNGYLLTGSCSMDD
Function
Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA). Can use other acyl donors, but with less efficiency. N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Ceramides generated by CERS6 play a role in inflammatory response. Acts as a regulator of metabolism and hepatic lipid accumulation. Under high fat diet, palmitoyl- (C16:0-) ceramides generated by CERS6 specifically bind the mitochondrial fission factor MFF, thereby promoting mitochondrial fragmentation and contributing to the development of obesity.
KEGG Pathway
Sphingolipid metabolism (hsa00600 )
Metabolic pathways (hsa01100 )
Sphingolipid sig.ling pathway (hsa04071 )
Reactome Pathway
Sphingolipid de novo biosynthesis (R-HSA-1660661 )
BioCyc Pathway
MetaCyc:ENSG00000172292-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Invasive breast carcinoma DISANYTW Definitive Biomarker [1]
Acute lymphocytic leukaemia DISPX75S Strong Biomarker [2]
Advanced cancer DISAT1Z9 Strong Biomarker [3]
Alcoholic liver diseases DISXEPHQ Strong Biomarker [4]
Childhood acute lymphoblastic leukemia DISJ5D6U Strong Biomarker [2]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [3]
Drug dependence DIS9IXRC Strong Biomarker [5]
Fatty liver disease DIS485QZ Strong Biomarker [4]
Head-neck squamous cell carcinoma DISF7P24 Strong Biomarker [6]
Lung cancer DISCM4YA Strong Biomarker [7]
Lung carcinoma DISTR26C Strong Biomarker [7]
Metabolic disorder DIS71G5H Strong Biomarker [8]
Mitochondrial disease DISKAHA3 Strong Biomarker [9]
Multiple sclerosis DISB2WZI Strong Altered Expression [10]
Neoplasm DISZKGEW Strong Biomarker [11]
Nervous system inflammation DISB3X5A Strong Biomarker [10]
Non-insulin dependent diabetes DISK1O5Z Strong Genetic Variation [12]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [7]
Substance abuse DIS327VW Strong Biomarker [5]
Substance dependence DISDRAAR Strong Biomarker [5]
T-cell acute lymphoblastic leukaemia DIS17AI2 Strong Biomarker [2]
Breast cancer DIS7DPX1 moderate Altered Expression [13]
Breast carcinoma DIS2UE88 moderate Altered Expression [13]
Graft-versus-host disease DIS0QADF moderate Biomarker [14]
Kennedy disease DISXZVM1 moderate Biomarker [15]
Colitis DISAF7DD Limited Altered Expression [16]
Gastric cancer DISXGOUK Limited Biomarker [11]
Melanoma DIS1RRCY Limited Biomarker [17]
Obesity DIS47Y1K Limited Biomarker [15]
Squamous cell carcinoma DISQVIFL Limited Biomarker [18]
Stomach cancer DISKIJSX Limited Biomarker [11]
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⏷ Show the Full List of 31 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
16 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Ceramide synthase 6 (CERS6). [19]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Ceramide synthase 6 (CERS6). [20]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Ceramide synthase 6 (CERS6). [21]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Ceramide synthase 6 (CERS6). [22]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Ceramide synthase 6 (CERS6). [23]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of Ceramide synthase 6 (CERS6). [24]
Marinol DM70IK5 Approved Marinol increases the expression of Ceramide synthase 6 (CERS6). [25]
Progesterone DMUY35B Approved Progesterone increases the expression of Ceramide synthase 6 (CERS6). [26]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Ceramide synthase 6 (CERS6). [27]
Resveratrol DM3RWXL Phase 3 Resveratrol increases the expression of Ceramide synthase 6 (CERS6). [28]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Ceramide synthase 6 (CERS6). [29]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Ceramide synthase 6 (CERS6). [30]
Geldanamycin DMS7TC5 Discontinued in Phase 2 Geldanamycin increases the expression of Ceramide synthase 6 (CERS6). [31]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Ceramide synthase 6 (CERS6). [32]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Ceramide synthase 6 (CERS6). [33]
GALLICACID DM6Y3A0 Investigative GALLICACID decreases the expression of Ceramide synthase 6 (CERS6). [34]
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⏷ Show the Full List of 16 Drug(s)

References

1 C16ceramide and sphingosine1phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation.Oncol Rep. 2018 Nov;40(5):2977-2987. doi: 10.3892/or.2018.6689. Epub 2018 Sep 7.
2 Ceramide synthase-6 confers resistance to chemotherapy by binding to CD95/Fas in T-cell acute lymphoblastic leukemia.Cell Death Dis. 2018 Sep 11;9(9):925. doi: 10.1038/s41419-018-0964-4.
3 Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer.Oncol Rep. 2018 Dec;40(6):3489-3500. doi: 10.3892/or.2018.6712. Epub 2018 Sep 18.
4 A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.FASEB J. 2018 Jan;32(1):130-142. doi: 10.1096/fj.201601142R. Epub 2017 Sep 1.
5 Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
6 Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways.FASEB J. 2010 Jan;24(1):296-308. doi: 10.1096/fj.09-135087. Epub 2009 Sep 1.
7 Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells.J Clin Invest. 2016 Jan;126(1):254-65. doi: 10.1172/JCI79775. Epub 2015 Dec 7.
8 CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity.Cell. 2019 May 30;177(6):1536-1552.e23. doi: 10.1016/j.cell.2019.05.008.
9 Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.Cell Death Dis. 2015 Mar 12;6(3):e1691. doi: 10.1038/cddis.2015.62.
10 Exacerbation of experimental autoimmune encephalomyelitis in ceramide synthase 6 knockout mice is associated with enhanced activation/migration of neutrophils.Immunol Cell Biol. 2015 Oct;93(9):825-36. doi: 10.1038/icb.2015.47. Epub 2015 Apr 2.
11 Ceramide synthase 6 predicts the prognosis of human gastric cancer: It functions as an oncoprotein by dysregulating the SOCS2/JAK2/STAT3 pathway.Mol Carcinog. 2018 Dec;57(12):1675-1689. doi: 10.1002/mc.22888. Epub 2018 Aug 29.
12 Noncoding Variations in the Gene Encoding Ceramide Synthase 6 are Associated with Type 2 Diabetes in a Large Indigenous Australian Pedigree.Twin Res Hum Genet. 2019 Apr;22(2):79-87. doi: 10.1017/thg.2019.13. Epub 2019 Apr 23.
13 Long noncoding RNA CERS6-AS1 functions as a malignancy promoter in breast cancer by binding to IGF2BP3 to enhance the stability of CERS6 mRNA.Cancer Med. 2020 Jan;9(1):278-289. doi: 10.1002/cam4.2675. Epub 2019 Nov 8.
14 Ceramide synthesis regulates T cell activity and GVHD development.JCI Insight. 2017 May 18;2(10):e91701. doi: 10.1172/jci.insight.91701. eCollection 2017 May 18.
15 The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach.Mol Metab. 2019 Mar;21:36-50. doi: 10.1016/j.molmet.2018.12.008. Epub 2019 Jan 2.
16 Ceramide Synthase 6 Deficiency Enhances Inflammation in the DSS model of Colitis.Sci Rep. 2018 Jan 26;8(1):1627. doi: 10.1038/s41598-018-20102-z.
17 Silencing of CerS6 increases the invasion and glycolysis of melanoma WM35, WM451 and SK28 cell lines via increased GLUT1-induced downregulation of WNT5A.Oncol Rep. 2016 May;35(5):2907-15. doi: 10.3892/or.2016.4646. Epub 2016 Mar 2.
18 CerS6 regulates cisplatin resistance in oral squamous cell carcinoma by altering mitochondrial fission and autophagy.J Cell Physiol. 2018 Dec;233(12):9416-9425. doi: 10.1002/jcp.26815. Epub 2018 Jul 27.
19 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
20 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
21 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
22 The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
23 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
24 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
25 Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy. 2016 Nov;12(11):2213-2229. doi: 10.1080/15548627.2016.1213927. Epub 2016 Sep 16.
26 Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
27 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
28 The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011 Feb;137(2):279-86. doi: 10.1007/s00432-010-0884-x. Epub 2010 Apr 18.
29 Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
30 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
31 Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
32 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
33 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
34 Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.