Details of Drug Off-Target (DOT)

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

• DOT Name: Ceramide synthase 2 (CERS2)
• Synonyms: CerS2; LAG1 longevity assurance homolog 2; SP260; Sphingosine N-acyltransferase CERS2; EC 2.3.1.24; Tumor metastasis-suppressor gene 1 protein; Very-long-chain ceramide synthase CERS2; EC 2.3.1.297
• Gene Name: CERS2
• Related Disease:
  Hyperglycemia
  Metastatic malignant neoplasm
  Prostate cancer
  Prostate carcinoma
  Rhegmatogenous retinal detachment
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Colitis
  Fatty liver disease
  Glioblastoma multiforme
  Inflammatory bowel disease
  Melanoma
  Multiple sclerosis
  Neoplasm
  Nervous system inflammation
  Non-alcoholic fatty liver disease
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Carcinoma
  Chronic kidney disease
  Thyroid gland papillary carcinoma
• UniProt ID: CERS2_HUMAN
• EC Number: 2.3.1.24; 2.3.1.297
• Pfam ID: PF00046 ; PF03798
• Sequence:
  MLQTLYDYFWWERLWLPVNLTWADLEDRDGRVYAKASDLYITLPLALLFLIVRYFFELYV
  ATPLAALLNIKEKTRLRAPPNATLEHFYLTSGKQPKQVEVELLSRQSGLSGRQVERWFRR
  RRNQDRPSLLKKFREASWRFTFYLIAFIAGMAVIVDKPWFYDMKKVWEGYPIQSTIPSQY
  WYYMIELSFYWSLLFSIASDVKRKDFKEQIIHHVATIILISFSWFANYIRAGTLIMALHD
  SSDYLLESAKMFNYAGWKNTCNNIFIVFAIVFIITRLVILPFWILHCTLVYPLELYPAFF
  GYYFFNSMMGVLQLLHIFWAYLILRMAHKFITGKLVEDERSDREETESSEGEEAAAGGGA
  KSRPLANGHPILNNNHRKND
• Function: Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very-long-chain fatty acyl-CoA (chain length C22-C27). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Plays a non-redundant role in the synthesis of ceramides with very-long-chain fatty acids in kidney, liver and brain. Regulates the abundance of myelin-specific sphingolipids galactosylceramide and sulfatide that affects myelin sheath architecture and motor neuron functions.
• Tissue Specificity: Expressed in kidney, liver, brain, heart, placenta and lung.
• 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:ENSG00000143418-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[2]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[3]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[3]
Rhegmatogenous retinal detachment	DISLE27J	Definitive	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Colitis	DISAF7DD	Strong	Biomarker	[8]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[10]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[8]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[11]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[13]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[14]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[15]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	moderate	Altered Expression	[16]
Chronic kidney disease	DISW82R7	moderate	Genetic Variation	[17]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Altered Expression	[18]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ceramide synthase 2 (CERS2).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ceramide synthase 2 (CERS2).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ceramide synthase 2 (CERS2).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ceramide synthase 2 (CERS2).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ceramide synthase 2 (CERS2).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ceramide synthase 2 (CERS2).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of Ceramide synthase 2 (CERS2).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ceramide synthase 2 (CERS2).	[26]

References

• [1] Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration.J Biomed Sci. 2018 May 2;25(1):40. doi: 10.1186/s12929-018-0437-1.
• [2] Clinical and pathological significance of Homo sapiens ceramide synthase 2 (CerS-2) in diverse human cancers.Biosci Rep. 2019 May 7;39(5):BSR20181743. doi: 10.1042/BSR20181743. Print 2019 May 31.
• [3] Silencing of vacuolar ATPase csubunit ATP6V0C inhibits the invasion of prostate cancer cells through a LASS2/TMSG1-independent manner.Oncol Rep. 2018 Jan;39(1):298-306. doi: 10.3892/or.2017.6092. Epub 2017 Nov 10.
• [4] Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment.Hum Mol Genet. 2013 Aug 1;22(15):3174-85. doi: 10.1093/hmg/ddt169. Epub 2013 Apr 11.
• [5] miR-3622a promotes proliferation and invasion of bladder cancer cells by downregulating LASS2.Gene. 2019 Jun 15;701:23-31. doi: 10.1016/j.gene.2019.02.083. Epub 2019 Mar 19.
• [6] CERS2 suppresses tumor cell invasion and is associated with decreased V-ATPase and MMP-2/MMP-9 activities in breast cancer.J Cell Biochem. 2015 Apr;116(4):502-13. doi: 10.1002/jcb.24978.
• [7] A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND.PLoS One. 2014 Sep 19;9(9):e106631. doi: 10.1371/journal.pone.0106631. eCollection 2014.
• [8] Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability.J Cell Mol Med. 2017 Dec;21(12):3565-3578. doi: 10.1111/jcmm.13267. Epub 2017 Jul 12.
• [9] Hepatocyte-specific deletion of LASS2 protects against diet-induced hepatic steatosis and insulin resistance.Free Radic Biol Med. 2018 May 20;120:330-341. doi: 10.1016/j.freeradbiomed.2018.04.003. Epub 2018 Apr 4.
• [10] Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5682-7. doi: 10.1073/pnas.1316700111. Epub 2014 Mar 31.
• [11] Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.Hum Mol Genet. 2011 Dec 15;20(24):5012-23. doi: 10.1093/hmg/ddr415. Epub 2011 Sep 17.
• [12] Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils.Brain Behav Immun. 2015 May;46:280-92. doi: 10.1016/j.bbi.2015.02.010. Epub 2015 Feb 16.
• [13] High expression of LASS2 is associated with unfavorable prognosis in patients with ovarian cancer.J Cell Physiol. 2019 Aug;234(8):13001-13013. doi: 10.1002/jcp.27970. Epub 2018 Dec 7.
• [14] Role of ceramide synthase 2 in G-CSF signaling and G-CSF-R translocation into detergent-resistant membranes.Sci Rep. 2019 Jan 24;9(1):747. doi: 10.1038/s41598-018-37342-8.
• [15] Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases.Exp Mol Med. 2019 Nov 1;51(11):1-16. doi: 10.1038/s12276-019-0340-1.
• [16] Expression profiles of proto-oncogene TWIST1 and tumor metastasis suppressor gene LASS2 in bladder cancer.Cell Mol Biol (Noisy-le-grand). 2018 Aug 30;64(11):66-73.
• [17] New loci associated with kidney function and chronic kidney disease.Nat Genet. 2010 May;42(5):376-84. doi: 10.1038/ng.568. Epub 2010 Apr 11.
• [18] Overexpression of LASS2 inhibits proliferation and causes G0/G1 cell cycle arrest in papillary thyroid cancer.Cancer Cell Int. 2018 Oct 1;18:151. doi: 10.1186/s12935-018-0649-1. eCollection 2018.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [21] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [24] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] 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.