Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUREU5Z)

• DOT Name: Collagen alpha-6(IV) chain (COL4A6)
• Synonyms: Collagen alpha-6(IV) chain
• Gene Name: COL4A6
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Kidney failure
  Leiomyoma
  Squamous cell carcinoma
  Uterine fibroids
  X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
  Prostate cancer
  Prostate carcinoma
  X-linked nonsyndromic hearing loss
  Adenoma
  Hearing loss, X-linked 6
  Neoplasm
  Premature ovarian failure 1
• UniProt ID: CO4A6_HUMAN
• Pfam ID: PF01413 ; PF01391
• Sequence:
  MLINKLWLLLVTLCLTEELAAAGEKSYGKPCGGQDCSGSCQCFPEKGARGRPGPIGIQGP
  TGPQGFTGSTGLSGLKGERGFPGLLGPYGPKGDKGPMGVPGFLGINGIPGHPGQPGPRGP
  PGLDGCNGTQGAVGFPGPDGYPGLLGPPGLPGQKGSKGDPVLAPGSFKGMKGDPGLPGLD
  GITGPQGAPGFPGAVGPAGPPGLQGPPGPPGPLGPDGNMGLGFQGEKGVKGDVGLPGPAG
  PPPSTGELEFMGFPKGKKGSKGEPGPKGFPGISGPPGFPGLGTTGEKGEKGEKGIPGLPG
  PRGPMGSEGVQGPPGQQGKKGTLGFPGLNGFQGIEGQKGDIGLPGPDVFIDIDGAVISGN
  PGDPGVPGLPGLKGDEGIQGLRGPSGVPGLPALSGVPGALGPQGFPGLKGDQGNPGRTTI
  GAAGLPGRDGLPGPPGPPGPPSPEFETETLHNKESGFPGLRGEQGPKGNLGLKGIKGDSG
  FCACDGGVPNTGPPGEPGPPGPWGLIGLPGLKGARGDRGSGGAQGPAGAPGLVGPLGPSG
  PKGKKGEPILSTIQGMPGDRGDSGSQGFRGVIGEPGKDGVPGLPGLPGLPGDGGQGFPGE
  KGLPGLPGEKGHPGPPGLPGNGLPGLPGPRGLPGDKGKDGLPGQQGLPGSKGITLPCIIP
  GSYGPSGFPGTPGFPGPKGSRGLPGTPGQPGSSGSKGEPGSPGLVHLPELPGFPGPRGEK
  GLPGFPGLPGKDGLPGMIGSPGLPGSKGATGDIFGAENGAPGEQGLQGLTGHKGFLGDSG
  LPGLKGVHGKPGLLGPKGERGSPGTPGQVGQPGTPGSSGPYGIKGKSGLPGAPGFPGISG
  HPGKKGTRGKKGPPGSIVKKGLPGLKGLPGNPGLVGLKGSPGSPGVAGLPALSGPKGEKG
  SVGFVGFPGIPGLPGIPGTRGLKGIPGSTGKMGPSGRAGTPGEKGDRGNPGPVGIPSPRR
  PMSNLWLKGDKGSQGSAGSNGFPGPRGDKGEAGRPGPPGLPGAPGLPGIIKGVSGKPGPP
  GFMGIRGLPGLKGSSGITGFPGMPGESGSQGIRGSPGLPGASGLPGLKGDNGQTVEISGS
  PGPKGQPGESGFKGTKGRDGLIGNIGFPGNKGEDGKVGVSGDVGLPGAPGFPGVAGMRGE
  PGLPGSSGHQGAIGPLGSPGLIGPKGFPGFPGLHGLNGLPGTKGTHGTPGPSITGVPGPA
  GLPGPKGEKGYPGIGIGAPGKPGLRGQKGDRGFPGLQGPAGLPGAPGISLPSLIAGQPGD
  PGRPGLDGERGRPGPAGPPGPPGPSSNQGDTGDPGFPGIPGPKGPKGDQGIPGFSGLPGE
  LGLKGMRGEPGFMGTPGKVGPPGDPGFPGMKGKAGPRGSSGLQGDPGQTPTAEAVQVPPG
  PLGLPGIDGIPGLTGDPGAQGPVGLQGSKGLPGIPGKDGPSGLPGPPGALGDPGLPGLQG
  PPGFEGAPGQQGPFGMPGMPGQSMRVGYTLVKHSQSEQVPPCPIGMSQLWVGYSLLFVEG
  QEKAHNQDLGFAGSCLPRFSTMPFIYCNINEVCHYARRNDKSYWLSTTAPIPMMPVSQTQ
  IPQYISRCSVCEAPSQAIAVHSQDITIPQCPLGWRSLWIGYSFLMHTAAGAEGGGQSLVS
  PGSCLEDFRATPFIECSGARGTCHYFANKYSFWLTTVEERQQFGELPVSETLKAGQLHTR
  VSRCQVCMKSL
• Function: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Relaxin sig.ling pathway (hsa04926)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Protein digestion and absorption (hsa04974)
  Amoebiasis (hsa05146)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Extracellular matrix organization (R-HSA-1474244)
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  Anchoring fibril formation (R-HSA-2214320)
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Laminin interactions (R-HSA-3000157)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  ECM proteoglycans (R-HSA-3000178)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[3]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[4]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[6]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[7]
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius	DIS6QXIR	Strong	Genetic Variation	[8]
Prostate cancer	DISF190Y	moderate	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[9]
X-linked nonsyndromic hearing loss	DISSWCJS	Supportive	X-linked	[10]
Adenoma	DIS78ZEV	Disputed	Genetic Variation	[1]
Hearing loss, X-linked 6	DISMTFI6	Limited	X-linked	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Premature ovarian failure 1	DISYHHEN	Limited	X-linked	[13]

3 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 Collagen alpha-6(IV) chain (COL4A6).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Collagen alpha-6(IV) chain (COL4A6).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Collagen alpha-6(IV) chain (COL4A6).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Collagen alpha-6(IV) chain (COL4A6).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Collagen alpha-6(IV) chain (COL4A6).	[18]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Collagen alpha-6(IV) chain (COL4A6).	[20]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[21]
Arecoline	DMFJZK3	Phase 1	Arecoline increases the expression of Collagen alpha-6(IV) chain (COL4A6).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Collagen alpha-6(IV) chain (COL4A6).	[27]

References

• [1] Exome capture sequencing of adenoma reveals genetic alterations in multiple cellular pathways at the early stage of colorectal tumorigenesis.PLoS One. 2013;8(1):e53310. doi: 10.1371/journal.pone.0053310. Epub 2013 Jan 2.
• [2] Comparative genomic analysis of collagen gene diversity.3 Biotech. 2019 Mar;9(3):83. doi: 10.1007/s13205-019-1616-9. Epub 2019 Feb 14.
• [3] Loss of expression of type IV collagen alpha5 and alpha6 chains in colorectal cancer associated with the hypermethylation of their promoter region.Am J Pathol. 2006 Mar;168(3):856-65. doi: 10.2353/ajpath.2006.050384.
• [4] Severe alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele.J Clin Invest. 1995 Apr;95(4):1832-7. doi: 10.1172/JCI117862.
• [5] Somatic deletion of the 5' ends of both the COL4A5 and COL4A6 genes in a sporadic leiomyoma of the esophagus.Am J Pathol. 1998 Mar;152(3):673-8.
• [6] The expression of type IV collagen alpha6 chain is related to the prognosis in patients with esophageal squamous cell carcinoma.Ann Surg Oncol. 2008 Feb;15(2):555-65. doi: 10.1245/s10434-007-9592-4. Epub 2007 Oct 23.
• [7] MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma.Mol Hum Reprod. 2018 Nov 1;24(11):556-563. doi: 10.1093/molehr/gay037.
• [8] Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes.Medicine (Baltimore). 1999 Sep;78(5):338-60. doi: 10.1097/00005792-199909000-00005.
• [9] Identification of new genes downregulated in prostate cancer and investigation of their effects on prognosis.Genet Test Mol Biomarkers. 2013 Jul;17(7):562-6. doi: 10.1089/gtmb.2012.0524. Epub 2013 Apr 27.
• [10] Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6. Eur J Hum Genet. 2014 Feb;22(2):208-15. doi: 10.1038/ejhg.2013.108. Epub 2013 May 29.
• [11] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [12] Deletions of both alpha 5(IV) and alpha 6(IV) collagen genes in Alport syndrome and in Alport syndrome associated with smooth muscle tumours.Hum Mol Genet. 1995 Jan;4(1):99-108. doi: 10.1093/hmg/4.1.99.
• [13] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [17] 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.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] Arecoline induces epithelial mesenchymal transition in HK2 cells by upregulating the ERK-mediated signaling pathway. Environ Toxicol. 2020 Sep;35(9):1007-1014. doi: 10.1002/tox.22937. Epub 2020 May 22.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] 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.
• [26] 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.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.