Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV2ZGV9)

• DOT Name: Serologically defined colon cancer antigen 8 (SDCCAG8)
• Synonyms: Antigen NY-CO-8; Centrosomal colon cancer autoantigen protein; hCCCAP
• Gene Name: SDCCAG8
• Related Disease:
  Retinopathy
  Senior-Loken syndrome 7
  Bardet-Biedl syndrome 16
  Chronic renal failure
  Ciliopathy
  End-stage renal disease
  Head and neck cancer
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  Intellectual disability
  Nephronophthisis
  Nephropathy
  Obesity
  Orofaciodigital syndrome
  Orofaciodigital syndrome I
  Retinitis pigmentosa
  Bipolar disorder
  Cystic kidney disease
  Schizoaffective disorder
  Bardet biedl syndrome
  Senior-Loken syndrome
  Polydactyly
• UniProt ID: SDCG8_HUMAN
• Pfam ID: PF15964
• Sequence:
  MAKSPENSTLEEILGQYQRSLREHASRSIHQLTCALKEGDVTIGEDAPNLSFSTSVGNED
  ARTAWPELQQSHAVNQLKDLLRQQADKESEVSPSRRRKMSPLRSLEHEETNMPTMHDLVH
  TINDQSQYIHHLEAEVKFCKEELSGMKNKIQVVVLENEGLQQQLKSQRQEETLREQTLLD
  ASGNMHNSWITTGEDSGVGETSKRPFSHDNADFGKAASAGEQLELEKLKLTYEEKCEIEE
  SQLKFLRNDLAEYQRTCEDLKEQLKHKEFLLAANTCNRVGGLCLKCAQHEAVLSQTHTNV
  HMQTIERLVKERDDLMSALVSVRSSLADTQQREASAYEQVKQVLQISEEANFEKTKALIQ
  CDQLRKELERQAERLEKELASQQEKRAIEKDMMKKEITKEREYMGSKMLILSQNIAQLEA
  QVEKVTKEKISAINQLEEIQSQLASREMDVTKVCGEMRYQLNKTNMEKDEAEKEHREFRA
  KTNRDLEIKDQEIEKLRIELDESKQHLEQEQQKAALAREECLRLTELLGESEHQLHLTRQ
  EKDSIQQSFSKEAKAQALQAQQREQELTQKIQQMEAQHDKTENEQYLLLTSQNTFLTKLK
  EECCTLAKKLEQISQKTRSEIAQLSQEKRYTYDKLGKLQRRNEELEEQCVQHGRVHETMK
  QRLRQLDKHSQATAQQLVQLLSKQNQLLLERQSLSEEVDRLRTQLPSMPQSDC
• Function: Plays a role in the establishment of cell polarity and epithelial lumen formation. Also plays an essential role in ciliogenesis and subsequent Hedgehog signaling pathway that requires the presence of intact primary cilia for pathway activation. Mechanistically, interacts with and mediates RABEP2 centrosomal localization which is critical for ciliogenesis.
• Tissue Specificity: Expressed in thymus, prostate, testis, ovary, small intestine, colon, mucosa, colon and renal cancer tumors.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinopathy	DISB4B0F	Definitive	Biomarker	[1]
Senior-Loken syndrome 7	DISJOZC5	Definitive	Autosomal recessive	[2]
Bardet-Biedl syndrome 16	DISVD0RT	Strong	Autosomal recessive	[3]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[4]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[5]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[4]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[6]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Biomarker	[7]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[4]
Nephropathy	DISXWP4P	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Genetic Variation	[4]
Orofaciodigital syndrome	DISSB296	Strong	Biomarker	[1]
Orofaciodigital syndrome I	DIST27XL	Strong	Biomarker	[1]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[8]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[9]
Cystic kidney disease	DISRT1LM	moderate	Biomarker	[1]
Schizoaffective disorder	DISLBW6B	moderate	Genetic Variation	[9]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[1]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[10]
Polydactyly	DIS25BMZ	Limited	Genetic Variation	[11]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serologically defined colon cancer antigen 8 (SDCCAG8).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Serologically defined colon cancer antigen 8 (SDCCAG8).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[13]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[21]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Serologically defined colon cancer antigen 8 (SDCCAG8).	[22]

References

• [1] Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet. 2010 Oct;42(10):840-50. doi: 10.1038/ng.662. Epub 2010 Sep 12.
• [2] Mutational analysis of SDCCAG8 in Bardet-Biedl syndrome patients with renal involvement and absent polydactyly. Ophthalmic Genet. 2012 Sep;33(3):150-4. doi: 10.3109/13816810.2012.689411. Epub 2012 May 24.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation.Tohoku J Exp Med. 2019 Sep;249(1):29-32. doi: 10.1620/tjem.249.29.
• [5] A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.Am J Hum Genet. 2018 Mar 1;102(3):375-400. doi: 10.1016/j.ajhg.2018.01.015. Epub 2018 Feb 15.
• [6] Sox11 promotes head and neck cancer progression via the regulation of SDCCAG8.J Exp Clin Cancer Res. 2019 Mar 29;38(1):138. doi: 10.1186/s13046-019-1146-7.
• [7] Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.Lancet. 2015 Apr 4;385(9975):1305-14. doi: 10.1016/S0140-6736(14)61705-0. Epub 2014 Dec 17.
• [8] Rare renal ciliopathies in non-consanguineous families that were identified by targeted resequencing.Clin Exp Nephrol. 2017 Feb;21(1):136-142. doi: 10.1007/s10157-016-1256-x. Epub 2016 Mar 11.
• [9] GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia / Bipolar susceptibility locus.Sci Rep. 2013 Oct 29;3:3075. doi: 10.1038/srep03075.
• [10] Senior-L?ken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis. Vision Res. 2012 Dec 15;75:88-97. doi: 10.1016/j.visres.2012.07.003. Epub 2012 Jul 20.
• [11] Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove mouse model.PLoS One. 2018 Feb 14;13(2):e0192755. doi: 10.1371/journal.pone.0192755. eCollection 2018.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [15] 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.
• [16] 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.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.