Details of Drug Off-Target (DOT)

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

• DOT Name: Collagen alpha-1(VI) chain (COL6A1)
• Synonyms: Collagen alpha-1(VI) chain
• Gene Name: COL6A1
• Related Disease:
  Collagen 6-related myopathy
  Astrocytoma
  Bethlem myopathy 1A
  Lung cancer
  Lung neoplasm
  Myopathy
  Obesity
  Ulcerative colitis
  Ullrich congenital muscular dystrophy 1A
  Hirschsprung disease
  Keratoconus
  Keratosis pilaris
  Limb-girdle muscular dystrophy
  Pancreatic cancer
  Bethlem myopathy
  Ullrich congenital muscular dystrophy
  Asthma
  Castration-resistant prostate carcinoma
  Chronic obstructive pulmonary disease
  Muscular dystrophy
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Trichothiodystrophy
• UniProt ID: CO6A1_HUMAN
• Pfam ID: PF01391 ; PF00092
• Sequence:
  MRAARALLPLLLQACWTAAQDEPETPRAVAFQDCPVDLFFVLDTSESVALRLKPYGALVD
  KVKSFTKRFIDNLRDRYYRCDRNLVWNAGALHYSDEVEIIQGLTRMPGGRDALKSSVDAV
  KYFGKGTYTDCAIKKGLEQLLVGGSHLKENKYLIVVTDGHPLEGYKEPCGGLEDAVNEAK
  HLGVKVFSVAITPDHLEPRLSIIATDHTYRRNFTAADWGQSRDAEEAISQTIDTIVDMIK
  NNVEQVCCSFECQPARGPPGLRGDPGFEGERGKPGLPGEKGEAGDPGRPGDLGPVGYQGM
  KGEKGSRGEKGSRGPKGYKGEKGKRGIDGVDGVKGEMGYPGLPGCKGSPGFDGIQGPPGP
  KGDPGAFGLKGEKGEPGADGEAGRPGSSGPSGDEGQPGEPGPPGEKGEAGDEGNPGPDGA
  PGERGGPGERGPRGTPGTRGPRGDPGEAGPQGDQGREGPVGVPGDPGEAGPIGPKGYRGD
  EGPPGSEGARGAPGPAGPPGDPGLMGERGEDGPAGNGTEGFPGFPGYPGNRGAPGINGTK
  GYPGLKGDEGEAGDPGDDNNDIAPRGVKGAKGYRGPEGPQGPPGHQGPPGPDECEILDII
  MKMCSCCECKCGPIDLLFVLDSSESIGLQNFEIAKDFVVKVIDRLSRDELVKFEPGQSYA
  GVVQYSHSQMQEHVSLRSPSIRNVQELKEAIKSLQWMAGGTFTGEALQYTRDQLLPPSPN
  NRIALVITDGRSDTQRDTTPLNVLCSPGIQVVSVGIKDVFDFIPGSDQLNVISCQGLAPS
  QGRPGLSLVKENYAELLEDAFLKNVTAQICIDKKCPDYTCPITFSSPADITILLDGSASV
  GSHNFDTTKRFAKRLAERFLTAGRTDPAHDVRVAVVQYSGTGQQRPERASLQFLQNYTAL
  ASAVDAMDFINDATDVNDALGYVTRFYREASSGAAKKRLLLFSDGNSQGATPAAIEKAVQ
  EAQRAGIEIFVVVVGRQVNEPHIRVLVTGKTAEYDVAYGESHLFRVPSYQALLRGVFHQT
  VSRKVALG
• Function: Collagen VI acts as a cell-binding protein.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Protein digestion and absorption (hsa04974)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Signaling by PDGF (R-HSA-186797)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  ECM proteoglycans (R-HSA-3000178)
  NCAM1 interactions (R-HSA-419037)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Collagen 6-related myopathy	DISF4E3M	Definitive	Autosomal dominant	[1]
Astrocytoma	DISL3V18	Strong	Altered Expression	[2]
Bethlem myopathy 1A	DIS0ATYV	Strong	Autosomal dominant	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Myopathy	DISOWG27	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[7]
Ullrich congenital muscular dystrophy 1A	DISFHHF0	Strong	Autosomal dominant	[3]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[8]
Keratoconus	DISOONXH	moderate	Genetic Variation	[9]
Keratosis pilaris	DISKOBPU	moderate	Genetic Variation	[10]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Genetic Variation	[11]
Pancreatic cancer	DISJC981	moderate	Biomarker	[12]
Bethlem myopathy	DISVF5K2	Supportive	Autosomal dominant	[13]
Ullrich congenital muscular dystrophy	DISJWD0V	Supportive	Autosomal dominant	[14]
Asthma	DISW9QNS	Limited	Biomarker	[15]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[16]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[15]
Muscular dystrophy	DISJD6P7	Limited	Biomarker	[17]
Neoplasm	DISZKGEW	Limited	Altered Expression	[16]
Prostate cancer	DISF190Y	Limited	Altered Expression	[16]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[16]
Trichothiodystrophy	DISOMQD2	Limited	Altered Expression	[18]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Collagen alpha-1(VI) chain (COL6A1) affects the response to substance of Topotecan.	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Collagen alpha-1(VI) chain (COL6A1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Collagen alpha-1(VI) chain (COL6A1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Collagen alpha-1(VI) chain (COL6A1).	[37]

24 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-1(VI) chain (COL6A1).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Collagen alpha-1(VI) chain (COL6A1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[25]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[27]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[21]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Collagen alpha-1(VI) chain (COL6A1).	[28]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[29]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Collagen alpha-1(VI) chain (COL6A1).	[30]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[31]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[21]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[38]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Collagen alpha-1(VI) chain (COL6A1).	[39]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[40]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone affects the expression of Collagen alpha-1(VI) chain (COL6A1).	[41]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Collagen alpha-1(VI) chain (COL6A1).	[21]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the secretion of Collagen alpha-1(VI) chain (COL6A1).	[34]
D-glucose	DMMG2TO	Investigative	D-glucose affects the secretion of Collagen alpha-1(VI) chain (COL6A1).	[34]

References

• [1] 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.
• [2] Identification of COL6A1 as a differentially expressed gene in human astrocytomas.Genet Mol Res. 2008 Apr 22;7(2):371-8. doi: 10.4238/vol7-2gmr432.
• [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] Proteomic analysis of differentially expressed proteins in lung cancer in Wistar rats using NNK as an inducer.Chem Biol Interact. 2013 Jul 5;204(2):125-34. doi: 10.1016/j.cbi.2013.05.004. Epub 2013 May 18.
• [5] Reductive Stress Selectively Disrupts Collagen Homeostasis and Modifies Growth Factor-independent Signaling Through the MAPK/Akt Pathway in Human Dermal Fibroblasts.Mol Cell Proteomics. 2019 Jun;18(6):1123-1137. doi: 10.1074/mcp.RA118.001140. Epub 2019 Mar 19.
• [6] Acute inflammation plays a limited role in the regulation of adipose tissue COL1A1 protein abundance.J Nutr Biochem. 2012 Jun;23(6):567-72. doi: 10.1016/j.jnutbio.2011.02.013. Epub 2011 Jul 19.
• [7] Contribution of Extracellular Matrix and Signal Mechanotransduction to Epithelial Cell Damage in Inflammatory Bowel Disease Patients: A Proteomic Study.Proteomics. 2017 Dec;17(23-24). doi: 10.1002/pmic.201700164. Epub 2017 Nov 29.
• [8] A collagen VI-dependent pathogenic mechanism for Hirschsprung's disease.J Clin Invest. 2015 Dec;125(12):4483-96. doi: 10.1172/JCI83178. Epub 2015 Nov 16.
• [9] Genetic Variants Associated With Corneal Biomechanical Properties and Potentially Conferring Susceptibility to Keratoconus in a Genome-Wide Association Study.JAMA Ophthalmol. 2019 Sep 1;137(9):1005-1012. doi: 10.1001/jamaophthalmol.2019.2058.
• [10] Expression of the collagen VI 5 and 6 chains in normal human skin and in skin of patients with collagen VI-related myopathies.J Invest Dermatol. 2011 Jan;131(1):99-107. doi: 10.1038/jid.2010.284. Epub 2010 Sep 30.
• [11] Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the spine.Ann Neurol. 2010 Feb;67(2):201-8. doi: 10.1002/ana.21846.
• [12] COL6A1 promotes metastasis and predicts poor prognosis in patients with pancreatic cancer.Int J Oncol. 2019 Aug;55(2):391-404. doi: 10.3892/ijo.2019.4825. Epub 2019 Jun 14.
• [13] Collagen VI-Related Dystrophies. 2004 Jun 25 [updated 2021 Mar 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [14] Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance. Hum Mutat. 2008 Jun;29(6):809-22. doi: 10.1002/humu.20704.
• [15] Toxicological effects of ambient fine (PM(2.5-0.18)) and ultrafine (PM(0.18)) particles in healthy and diseased 3D organo-typic mucocilary-phenotype models.Environ Res. 2019 Sep;176:108538. doi: 10.1016/j.envres.2019.108538. Epub 2019 Jun 15.
• [16] Reactive stroma component COL6A1 is upregulated in castration-resistant prostate cancer and promotes tumor growth.Oncotarget. 2015 Jun 10;6(16):14488-96. doi: 10.18632/oncotarget.3697.
• [17] A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies.JCI Insight. 2019 Mar 21;4(6):e124403. doi: 10.1172/jci.insight.124403. eCollection 2019 Mar 21.
• [18] XPD mutations in trichothiodystrophy hamper collagen VI expression and reveal a role of TFIIH in transcription derepression.Hum Mol Genet. 2013 Mar 15;22(6):1061-73. doi: 10.1093/hmg/dds508. Epub 2012 Dec 5.
• [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] 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] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [25] 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.
• [26] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [27] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [28] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [29] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [30] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [31] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [32] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [40] Methylparaben-induced decrease in collagen production and viability of cultured human dermal fibroblasts. J Appl Toxicol. 2017 Sep;37(9):1117-1124. doi: 10.1002/jat.3466. Epub 2017 Apr 6.
• [41] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [42] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.