Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHQI7IY)

• DOT Name: Mucin-1 (MUC1)
• Synonyms: MUC-1; Breast carcinoma-associated antigen DF3; Cancer antigen 15-3; CA 15-3; Carcinoma-associated mucin; Episialin; H23AG; Krebs von den Lungen-6; KL-6; PEMT; Peanut-reactive urinary mucin; PUM; Polymorphic epithelial mucin; PEM; Tumor-associated epithelial membrane antigen; EMA; Tumor-associated mucin; CD antigen CD227
• Gene Name: MUC1
• Related Disease: Tubulointerstitial kidney disease, autosomal dominant, 2
• UniProt ID: MUC1_HUMAN
• PDB ID: 1SM3; 2ACM; 2FO4; 5T6P; 5T78; 6FZQ; 6FZR; 6KX1; 6TGG; 7Q4I; 7V4W; 7V64; 7V7K; 7V8Q; 7VAC; 7VAZ; 8AXH
• Pfam ID: PF01390
• Sequence:
  MTPGTQSPFFLLLLLTVLTVVTGSGHASSTPGGEKETSATQRSSVPSSTEKNAVSMTSSV
  LSSHSPGSGSSTTQGQDVTLAPATEPASGSAATWGQDVTSVPVTRPALGSTTPPAHDVTS
  APDNKPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTS
  APDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAPDNRPALGSTAPPVHNVTS
  ASGSASGSASTLVHNGTSARATTTPASKSTPFSIPSHHSDTPTTLASHSTKTDASSTHHS
  SVPPLTSSNHSTSPQLSTGVSFFFLSFHISNLQFNSSLEDPSTDYYQELQRDISEMFLQI
  YKQGGFLGLSNIKFRPGSVVVQLTLAFREGTINVHDVETQFNQYKTEAASRYNLTISDVS
  VSDVPFPFSAQSGAGVPGWGIALLVLVCVLVALAIVYLIALAVCQCRRKNYGQLDIFPAR
  DTYHPMSEYPTYHTHGRYVPPSSTDRSPYEKVSAGNGGSSLSYTNPAVAATSANL
• Function: The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.; The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.
• Tissue Specificity: Expressed on the apical surface of epithelial cells, especially of airway passages, breast and uterus. Also expressed in activated and unactivated T-cells. Overexpressed in epithelial tumors, such as breast or ovarian cancer and also in non-epithelial tumor cells. Isoform Y is expressed in tumor cells only.
• Reactome Pathway:
  Defective C1GALT1C1 causes TNPS (R-HSA-5083632)
  Defective GALNT12 causes CRCS1 (R-HSA-5083636)
  Dectin-2 family (R-HSA-5621480)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  O-linked glycosylation of mucins (R-HSA-913709)
  Termination of O-glycan biosynthesis (R-HSA-977068)
  Defective GALNT3 causes HFTC (R-HSA-5083625)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tubulointerstitial kidney disease, autosomal dominant, 2	DISRRBM2	Definitive	Autosomal dominant	[1]

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 Mucin-1 (MUC1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mucin-1 (MUC1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mucin-1 (MUC1).	[24]

26 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 Mucin-1 (MUC1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mucin-1 (MUC1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mucin-1 (MUC1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mucin-1 (MUC1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mucin-1 (MUC1).	[7]
Progesterone	DMUY35B	Approved	Progesterone affects the expression of Mucin-1 (MUC1).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mucin-1 (MUC1).	[9]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Mucin-1 (MUC1).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mucin-1 (MUC1).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Mucin-1 (MUC1).	[12]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Mucin-1 (MUC1).	[13]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Mucin-1 (MUC1).	[14]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of Mucin-1 (MUC1).	[15]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of Mucin-1 (MUC1).	[3]
Vandetanib	DMRICNP	Approved	Vandetanib increases the expression of Mucin-1 (MUC1).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Mucin-1 (MUC1).	[17]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Mucin-1 (MUC1).	[18]
I3C	DMIGFOR	Phase 3	I3C decreases the expression of Mucin-1 (MUC1).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mucin-1 (MUC1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mucin-1 (MUC1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mucin-1 (MUC1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mucin-1 (MUC1).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Mucin-1 (MUC1).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Mucin-1 (MUC1).	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mucin-1 (MUC1).	[3]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Mucin-1 (MUC1).	[27]

References

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• [2] 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.
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• [4] Retinoic acid can induce markers of endocrine transdifferentiation in pancreatic ductal adenocarcinoma: preliminary observations from an in vitro cell line model. J Clin Pathol. 2006 Jun;59(6):603-10. doi: 10.1136/jcp.2005.032003. Epub 2006 Feb 10.
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• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] The expression pattern of MUC1 glycoforms and other biomarkers of endometrial receptivity in fertile and infertile women. Mol Reprod Dev. 2005 Oct;72(2):216-29. doi: 10.1002/mrd.20307.
• [9] Muc-1 core protein is expressed on multiple myeloma cells and is induced by dexamethasone. Blood. 1999 Feb 15;93(4):1287-98.
• [10] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [14] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [15] Effects of retinoids on cancerous phenotype and apoptosis in organotypic cultures of ovarian carcinoma. J Natl Cancer Inst. 2001 Apr 4;93(7):516-25. doi: 10.1093/jnci/93.7.516.
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• [17] Effects of resveratrol on gene expression in renal cell carcinoma. Cancer Biol Ther. 2004 Sep;3(9):882-8. doi: 10.4161/cbt.3.9.1056. Epub 2004 Sep 21.
• [18] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [19] Inhibition of MUC1 expression by indole-3-carbinol. Int J Cancer. 2004 May 10;109(6):810-6. doi: 10.1002/ijc.20031.
• [20] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [21] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [27] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.