Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPVL723)

• DOT Name: Mucin-6 (MUC6)
• Synonyms: MUC-6; Gastric mucin-6
• Gene Name: MUC6
• Related Disease:
  Adenoma
  Advanced cancer
  Anal intraepithelial neoplasia
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cholangiocarcinoma
  Chronic obstructive pulmonary disease
  Colorectal adenoma
  Colorectal carcinoma
  Cystic fibrosis
  Endometrial carcinoma
  Endometrium adenocarcinoma
  Familial adenomatous polyposis
  Familial multiple trichoepithelioma
  Gastric adenocarcinoma
  Gastric neoplasm
  Gastric ulcer
  Hereditary diffuse gastric adenocarcinoma
  Intrahepatic cholangiocarcinoma
  Invasive ductal breast carcinoma
  Lung cancer
  Lung carcinoma
  Malignant soft tissue neoplasm
  Nasal polyp
  Pancreatic cancer
  Pancreatic tumour
  Polyp
  Prostate neoplasm
  Pulmonary arterial hypertension
  Sarcoma
  Stomach cancer
  Ulcerative colitis
  Gastric cancer
  Duodenal ulcer
  Colon adenocarcinoma
  Inflammatory bowel disease
  Lung adenocarcinoma
  Minimally invasive lung adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Rectal carcinoma
• UniProt ID: MUC6_HUMAN
• Pfam ID: PF08742 ; PF01826 ; PF00094
• Sequence:
  MVQRWLLLSCCGALLSAGLANTSYTSPGLQRLKDSPQTAPDKGQCSTWGAGHFSTFDHHV
  YDFSGTCNYIFAATCKDAFPTFSVQLRRGPDGSISRIIVELGASVVTVSEAIISVKDIGV
  ISLPYTSNGLQITPFGQSVRLVAKQLELELEVVWGPDSHLMVLVERKYMGQMCGLCGNFD
  GKVTNEFVSEEGKFLEPHKFAALQKLDDPGEICTFQDIPSTHVRQAQHARICTQLLTLVA
  PECSVSKEPFVLSCQADVAAAPQPGPQNSSCATLSEYSRQCSMVGQPVRRWRSPGLCSVG
  QCPANQVYQECGSACVKTCSNPQHSCSSSCTFGCFCPEGTVLNDLSNNHTCVPVTQCPCV
  LHGAMYAPGEVTIAACQTCRCTLGRWVCTERPCPGHCSLEGGSFVTTFDARPYRFHGTCT
  YILLQSPQLPEDGALMAVYDKSGVSHSETSLVAVVYLSRQDKIVISQDEVVTNNGEAKWL
  PYKTRNITVFRQTSTHLQMATSFGLELVVQLRPIFQAYVTVGPQFRGQTRGLCGNFNGDT
  TDDFTTSMGIAEGTASLFVDSWRAGNCPAALERETDPCSMSQLNKVCAETHCSMLLRTGT
  VFERCHATVNPAPFYKRCVYQACNYEETFPHICAALGDYVHACSLRGVLLWGWRSSVDNC
  TIPCTGNTTFSYNSQACERTCLSLSDRATECHHSAVPVDGCNCPDGTYLNQKGECVRKAQ
  CPCILEGYKFILAEQSTVINGITCHCINGRLSCPQRPQMFLASCQAPKTFKSCSQSSENK
  FGAACAPTCQMLATGVACVPTKCEPGCVCAEGLYENADGQCVPPEECPCEFSGVSYPGGA
  ELHTDCRTCSCSRGRWACQQGTHCPSTCTLYGEGHVITFDGQRFVFDGNCEYILATDVCG
  VNDSQPTFKILTENVICGNSGVTCSRAIKIFLGGLSVVLADRNYTVTGEEPHVQLGVTPG
  ALSLVVDISIPGRYNLTLIWNRHMTILIRIARASQDPLCGLCGNFNGNMKDDFETRSRYV
  ASSELELVNSWKESPLCGDVSFVTDPCSLNAFRRSWAERKCSVINSQTFATCHSKVYHLP
  YYEACVRDACGCDSGGDCECLCDAVAAYAQACLDKGVCVDWRTPAFCPIYCGFYNTHTQD
  GHGEYQYTQEANCTWHYQPCLCPSQPQSVPGSNIEGCYNCSQDEYFDHEEGVCVPCMPPT
  TPQPPTTPQLPTTGSRPTQVWPMTGTSTTIGLLSSTGPSPSSNHTPASPTQTPLLPATLT
  SSKPTASSGEPPRPTTAVTPQATSGLPPTATLRSTATKPTVTQATTRATASTASPATTST
  AQSTTRTTMTLPTPATSGTSPTLPKSTNQELPGTTATQTTGPRPTPASTTGPTTPQPGQP
  TRPTATETTQTRTTTEYTTPQTPHTTHSPPTAGSPVPSTGPVTATSFHATTTYPTPSHPE
  TTLPTHVPPFSTSLVTPSTHTVITPTHAQMATSASNHSAPTGTIPPPTTLKATGSTHTAP
  PITPTTSGTSQAHSSFSTNKTPTSLHSHTSSTHHPEVTPTSTTTITPNPTSTRTRTPVAH
  TNSATSSRPPPPFTTHSPPTGSSPFSSTGPMTATSFKTTTTYPTPSHPQTTLPTHVPPFS
  TSLVTPSTHTVITPTHAQMATSASIHSMPTGTIPPPTTLKATGSTHTAPTMTLTTSGTSQ
  ALSSLNTAKTSTSLHSHTSSTHHAEATSTSTTNITPNPTSTGTPPMTVTTSGTSQSRSSF
  STAKTSTSLHSHTSSTHHPEVTSTSTTSITPNHTSTGTRTPVAHTTSATSSRLPTPFTTH
  SPPTGTTPISSTGPVTATSFQTTTTYPTPSHPHTTLPTHVPSFSTSLVTPSTHTVIIPTH
  TQMATSASIHSMPTGTIPPPTTIKATGSTHTAPPMTPTTSGTSQSPSSFSTAKTSTSLPY
  HTSSTHHPEVTPTSTTNITPKHTSTGTRTPVAHTTSASSSRLPTPFTTHSPPTGSSPFSS
  TGPMTATSFQTTTTYPTPSHPQTTLPTHVPPFSTSLVTPSTHTVIITTHTQMATSASIHS
  TPTGTVPPPTTLKATGSTHTAPPMTVTTSGTSQTHSSFSTATASSSFISSSSWLPQNSSS
  RPPSSPITTQLPHLSSATTPVSTTNQLSSSFSPSPSAPSTVSSYVPSSHSSPQTSSPSVG
  TSSSFVSAPVHSTTLSSGSHSSLSTHPTTASVSASPLFPSSPAASTTIRATLPHTISSPF
  TLSALLPISTVTVSPTPSSHLASSTIAFPSTPRTTASTHTAPAFSSQSTTSRSTSLTTRV
  PTSGFVSLTSGVTGIPTSPVTNLTTRHPGPTLSPTTRFLTSSLTAHGSTPASAPVSSLGT
  PTPTSPGVCSVREQQEEITFKGCMANVTVTRCEGACISAASFNIITQQVDARCSCCRPLH
  SYEQQLELPCPDPSTPGRRLVLTLQVFSHCVCSSVACGD
• Function: May provide a mechanism for modulation of the composition of the protective mucus layer related to acid secretion or the presence of bacteria and noxious agents in the lumen. Plays an important role in the cytoprotection of epithelial surfaces and are used as tumor markers in a variety of cancers. May play a role in epithelial organogenesis.
• Tissue Specificity: Expressed in the regenerative zone of gastric antrum, gastric body mucosa and gastric incisura mucosa. Expressed in the deeper mucous glands of gastric antrum. Overexpressed in Helicobacter pylori infected gastric epithelium. Highly expressed in duodenal Brunner's glands, gall bladder, seminal vesicle, pancreatic centroacinar cells and ducts, and periductal glands of the common bile duct.
• Reactome Pathway:
  Defective C1GALT1C1 causes TNPS (R-HSA-5083632)
  Defective GALNT12 causes CRCS1 (R-HSA-5083636)
  Dectin-2 family (R-HSA-5621480)
  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

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Altered Expression	[3]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[9]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[12]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[13]
Endometrium adenocarcinoma	DISY6744	Strong	Altered Expression	[14]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[15]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[16]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[17]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[18]
Gastric ulcer	DISBBGVO	Strong	Biomarker	[19]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[18]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[20]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[21]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[22]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[23]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[21]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[24]
Polyp	DISRSLYF	Strong	Genetic Variation	[25]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[26]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Genetic Variation	[27]
Sarcoma	DISZDG3U	Strong	Biomarker	[22]
Stomach cancer	DISKIJSX	Strong	Biomarker	[17]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[28]
Gastric cancer	DISXGOUK	moderate	Biomarker	[18]
Duodenal ulcer	DISNHHCN	Disputed	Biomarker	[19]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[29]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[30]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[31]
Minimally invasive lung adenocarcinoma	DIS4W83X	Limited	Altered Expression	[31]
Prostate cancer	DISF190Y	Limited	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[26]
Rectal carcinoma	DIS8FRR7	Limited	Genetic Variation	[32]

4 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-6 (MUC6).	[33]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mucin-6 (MUC6).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mucin-6 (MUC6).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mucin-6 (MUC6).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mucin-6 (MUC6).	[34]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mucin-6 (MUC6).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mucin-6 (MUC6).	[38]

References

• [1] Serrated adenoma of the stomach: a clinicopathologic, immunohistochemical, and molecular study of nine cases.Histol Histopathol. 2013 Apr;28(4):453-62. doi: 10.14670/HH-28.453. Epub 2013 Feb 13.
• [2] Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in ALK-positive lung cancer: Comparison with EGFR-mutated lung cancer.Pathol Res Pract. 2019 Mar;215(3):459-465. doi: 10.1016/j.prp.2018.12.011. Epub 2018 Dec 10.
• [3] Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas.Gastroenterology. 2002 Oct;123(4):1052-60. doi: 10.1053/gast.2002.36018.
• [4] Cdx2 expression and its promoter methylation during metaplasia-dysplasia-carcinoma sequence in Barrett's esophagus.World J Gastroenterol. 2013 Jan 28;19(4):536-41. doi: 10.3748/wjg.v19.i4.536.
• [5] Lynch syndrome-associated breast cancers do not overexpress chromosome 11-encoded mucins.Mod Pathol. 2013 Jul;26(7):944-54. doi: 10.1038/modpathol.2012.232. Epub 2013 Feb 1.
• [6] Immunohistochemical analysis of MUC5B apomucin expression in breast cancer and non-malignant breast tissues.J Histochem Cytochem. 2006 Mar;54(3):289-99. doi: 10.1369/jhc.5A6763.2005. Epub 2005 Sep 7.
• [7] Colitis-associated colorectal adenocarcinomas are frequently associated with non-intestinal mucin profiles and loss of SATB2 expression.Mod Pathol. 2019 Jun;32(6):884-892. doi: 10.1038/s41379-018-0198-0. Epub 2019 Feb 1.
• [8] The MUC6 secretory mucin gene is expressed in a wide variety of epithelial tissues.J Pathol. 1998 Dec;186(4):398-405. doi: 10.1002/(SICI)1096-9896(199812)186:4<398::AID-PATH192>3.0.CO;2-X.
• [9] Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease.Histopathology. 2004 Nov;45(5):477-84. doi: 10.1111/j.1365-2559.2004.01952.x.
• [10] Abnormal subcellular distribution of mature MUC2 and de novo MUC5AC mucins in adenomas of the rectum: immunohistochemical detection using non-VNTR antibodies to MUC2 and MUC5AC peptide.Glycoconj J. 2001 Nov-Dec;18(11-12):907-14. doi: 10.1023/a:1022204626604.
• [11] Aberrant expression of annexin A10 is closely related to gastric phenotype in serrated pathway to colorectal carcinoma.Mod Pathol. 2015 Feb;28(2):268-78. doi: 10.1038/modpathol.2014.96. Epub 2014 Aug 1.
• [12] Cystic fibrosis of the pancreas: involvement of MUC6 mucin in obstruction of pancreatic ducts.Mol Med. 1997 Jun;3(6):403-11.
• [13] Immunohistochemical expression of HIK1083 and MUC6 in endometrial carcinomas.Histopathology. 2019 Oct;75(4):552-558. doi: 10.1111/his.13887. Epub 2019 Aug 8.
• [14] Mucin genes (MUC2, MUC4, MUC5AC, and MUC6) detection in normal and pathological endometrial tissues.Int J Gynecol Pathol. 2007 Jan;26(1):61-5. doi: 10.1097/01.pgp.0000225837.32719.c1.
• [15] Oncocytic papillary neoplasms of the biliary tract: a clinicopathological, mucin core and Wnt pathway protein analysis of four cases.Pathology. 2007 Aug;39(4):413-8. doi: 10.1080/00313020701444531.
• [16] Mucin Expression in the Esophageal Malignant and Pre-malignant States: A Systematic Review and Meta-analysis.J Clin Gastroenterol. 2018 Feb;52(2):91-96. doi: 10.1097/MCG.0000000000000863.
• [17] Loss of gastric gland mucin-specific O-glycan is associated with progression of differentiated-type adenocarcinoma of the stomach.Cancer Sci. 2014 Jan;105(1):126-33. doi: 10.1111/cas.12305. Epub 2013 Nov 22.
• [18] Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.Nat Genet. 2014 Jun;46(6):573-82. doi: 10.1038/ng.2983. Epub 2014 May 11.
• [19] Quantitative MUC5AC and MUC6 mucin estimations in gastric mucus by a least-squares minimization method.Anal Biochem. 2013 Aug 15;439(2):204-11. doi: 10.1016/j.ab.2013.04.013. Epub 2013 Apr 30.
• [20] Mucinous intrahepatic cholangiocarcinoma: a distinct variant.Hum Pathol. 2018 Aug;78:131-137. doi: 10.1016/j.humpath.2018.04.010. Epub 2018 Apr 23.
• [21] Gastric gland mucin-specific O-glycan expression decreases with tumor progression from precursor lesions to pancreatic cancer.Cancer Sci. 2017 Sep;108(9):1897-1902. doi: 10.1111/cas.13317. Epub 2017 Aug 8.
• [22] MUC5AC/-catenin expression and KRAS gene alteration in laterally spreading colorectal tumors.World J Gastroenterol. 2012 Oct 21;18(39):5551-9. doi: 10.3748/wjg.v18.i39.5551.
• [23] Mucin gene expression in nasal polyps.Acta Otolaryngol. 2005 Jun;125(6):618-24. doi: 10.1080/00016480510027538.
• [24] Gastric gland mucin-specific O-glycan expression decreases as tumor cells progress from lobular endocervical gland hyperplasia to cervical mucinous carcinoma, gastric type.Virchows Arch. 2018 Sep;473(3):305-311. doi: 10.1007/s00428-018-2381-6. Epub 2018 May 29.
• [25] Clinicopathological factors associated with BRAF-V600E mutation in colorectal serrated adenomas.Histopathology. 2019 Aug;75(2):160-173. doi: 10.1111/his.13846. Epub 2019 May 16.
• [26] MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer.Clin Exp Metastasis. 2005;22(7):565-73. doi: 10.1007/s10585-005-5376-z. Epub 2006 Feb 11.
• [27] Identification of a low frequency missense mutation in MUC6 contributing to pulmonary artery hypertension by whole-exome sequencing.Pulm Circ. 2018 Jul-Sep;8(3):2045894018794374. doi: 10.1177/2045894018794374. Epub 2018 Jul 26.
• [28] Alterations in the composition of the supramucosal defense barrier in relation to disease severity of ulcerative colitis.J Histochem Cytochem. 2006 Dec;54(12):1335-48. doi: 10.1369/jhc.5A6904.2006. Epub 2006 Aug 21.
• [29] Expression of mucin genes and carbohydrate epitopes in 19 human colon carcinoma cell lines.Oncol Res. 1998;10(8):407-14.
• [30] The central exons of the human MUC2 and MUC6 mucins are highly repetitive and variable in sequence between individuals.Sci Rep. 2018 Nov 30;8(1):17503. doi: 10.1038/s41598-018-35499-w.
• [31] Expression of MUC1, MUC2, MUC5AC, and MUC6 in atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, adenocarcinoma with mixed subtypes, and mucinous bronchioloalveolar carcinoma of the lung.Am J Clin Pathol. 2004 May;121(5):644-53. doi: 10.1309/U4WG-E9EB-FJN6-CM8R.
• [32] Association of MUC6-minisatellite variants with susceptibility to rectal carcinoma.Mol Biol Rep. 2013 Jan;40(1):303-8. doi: 10.1007/s11033-012-2062-5. Epub 2012 Oct 10.
• [33] 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.
• [34] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [35] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [36] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [37] 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.
• [38] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [39] 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.