Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQVI1EM)

• DOT Name: Colorectal mutant cancer protein (MCC)
• Synonyms: Protein MCC
• Gene Name: MCC
• Related Disease:
  Acute myelogenous leukaemia
  Narcolepsy
  Adenocarcinoma
  Adenoma
  Anaplastic large cell lymphoma
  Asthma
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Carcinoma
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Familial adenomatous polyposis
  Gastric adenocarcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Intestinal neoplasm
  Liver cirrhosis
  Lung neoplasm
  Melanoma
  Multiple sclerosis
  Neoplasm
  Neuralgia
  Non-insulin dependent diabetes
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Sickle-cell anaemia
  Small-cell lung cancer
  Thrombocytopenia
  Autism
  Familial adenomatous polyposis 1
  Gastric cancer
  Intellectual disability
  Rectal carcinoma
  Rectal neoplasm
  Stomach cancer
  Esophageal cancer
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Oral cancer
  Small lymphocytic lymphoma
  Squamous cell carcinoma
• UniProt ID: CRCM_HUMAN
• PDB ID: 6MTU; 6MTV
• Pfam ID: PF10506
• Sequence:
  MNSGVAMKYGNDSSAELSELHSAALASLKGDIVELNKRLQQTERERDLLEKKLAKAQCEQ
  SHLMREHEDVQERTTLRYEERITELHSVIAELNKKIDRLQGTTIREEDEYSELRSELSQS
  QHEVNEDSRSMDQDQTSVSIPENQSTMVTADMDNCSDLNSELQRVLTGLENVVCGRKKSS
  CSLSVAEVDKHIEQLTTASEHCDLAIKTVEEIEGVLGRDLYPNLAEERSRWEKELAGLRE
  ENESLTAMLCSKEEELNRTKATMNAIREERDRLRRRVRELQTRLQSVQATGPSSPGRLTS
  TNRPINPSTGELSTSSSSNDIPIAKIAERVKLSKTRSESSSSDRPVLGSEISSIGVSSSV
  AEHLAHSLQDCSNIQEIFQTLYSHGSAISESKIREFEVETERLNSRIEHLKSQNDLLTIT
  LEECKSNAERMSMLVGKYESNATALRLALQYSEQCIEAYELLLALAESEQSLILGQFRAA
  GVGSSPGDQSGDENITQMLKRAHDCRKTAENAAKALLMKLDGSCGGAFAVAGCSVQPWES
  LSSNSHTSTTSSTASSCDTEFTKEDEQRLKDYIQQLKNDRAAVKLTMLELESIHIDPLSY
  DVKPRGDSQRLDLENAVLMQELMAMKEEMAELKAQLYLLEKEKKALELKLSTREAQEQAY
  LVHIEHLKSEVEEQKEQRMRSLSSTSSGSKDKPGKECADAASPALSLAELRTTCSENELA
  AEFTNAIRREKKLKARVQELVSALERLTKSSEIRHQQSAEFVNDLKRANSNLVAAYEKAK
  KKHQNKLKKLESQMMAMVERHETQVRMLKQRIALLEEENSRPHTNETSL
• Function: Candidate for the putative colorectal tumor suppressor gene located at 5q21. Suppresses cell proliferation and the Wnt/b-catenin pathway in colorectal cancer cells. Inhibits DNA binding of b-catenin/TCF/LEF transcription factors. Involved in cell migration independently of RAC1, CDC42 and p21-activated kinase (PAK) activation. Represses the beta-catenin pathway (canonical Wnt signaling pathway) in a CCAR2-dependent manner by sequestering CCAR2 to the cytoplasm, thereby impairing its ability to inhibit SIRT1 which is involved in the deacetylation and negative regulation of beta-catenin (CTNB1) transcriptional activity.
• Tissue Specificity: Expressed in a variety of tissues.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[2]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[5]
Asthma	DISW9QNS	Strong	Genetic Variation	[6]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[7]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[10]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[12]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[13]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Inflammatory bowel disease	DISGN23E	Strong	Posttranslational Modification	[16]
Intestinal neoplasm	DISK0GUH	Strong	Biomarker	[17]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[18]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[19]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[20]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Neuralgia	DISWO58J	Strong	Biomarker	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[23]
Pancreatic cancer	DISJC981	Strong	Biomarker	[24]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[25]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[25]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[26]
Sickle-cell anaemia	DIS5YNZB	Strong	Genetic Variation	[27]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[28]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[29]
Autism	DISV4V1Z	moderate	Biomarker	[30]
Familial adenomatous polyposis 1	DISM44VR	moderate	Biomarker	[30]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[31]
Intellectual disability	DISMBNXP	moderate	Biomarker	[30]
Rectal carcinoma	DIS8FRR7	moderate	Biomarker	[30]
Rectal neoplasm	DISB4UZ0	moderate	Biomarker	[30]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[31]
Esophageal cancer	DISGB2VN	Disputed	Genetic Variation	[32]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[33]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[34]
Oral cancer	DISLD42D	Limited	Genetic Variation	[35]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[36]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[35]

2 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 Colorectal mutant cancer protein (MCC).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Colorectal mutant cancer protein (MCC).	[47]

15 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 Colorectal mutant cancer protein (MCC).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Colorectal mutant cancer protein (MCC).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Colorectal mutant cancer protein (MCC).	[40]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Colorectal mutant cancer protein (MCC).	[41]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Colorectal mutant cancer protein (MCC).	[42]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Colorectal mutant cancer protein (MCC).	[42]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Colorectal mutant cancer protein (MCC).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Colorectal mutant cancer protein (MCC).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Colorectal mutant cancer protein (MCC).	[44]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Colorectal mutant cancer protein (MCC).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Colorectal mutant cancer protein (MCC).	[46]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Colorectal mutant cancer protein (MCC).	[48]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Colorectal mutant cancer protein (MCC).	[49]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Colorectal mutant cancer protein (MCC).	[50]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Colorectal mutant cancer protein (MCC).	[51]

References

• [1] Detection of prognostic methylation markers by methylC-capture sequencing in acute myeloid leukemia.Oncotarget. 2017 Nov 30;8(66):110444-110459. doi: 10.18632/oncotarget.22789. eCollection 2017 Dec 15.
• [2] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [3] Allelic loss involving the tumor suppressor genes APC and MCC and expression of the APC protein in the development of dysplasia and carcinoma in Barrett esophagus.Am J Clin Pathol. 2000 Dec;114(6):890-5. doi: 10.1309/L1Q3-E3AQ-APU9-NA0A.
• [4] Distinct WNT/-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum.Mod Pathol. 2015 Jan;28(1):146-58. doi: 10.1038/modpathol.2014.41. Epub 2014 Jun 13.
• [5] Conjugation of DM1 to anti-CD30 antibody has potential antitumor activity in CD30-positive hematological malignancies with lower systemic toxicity.MAbs. 2019 Aug/Sep;11(6):1149-1161. doi: 10.1080/19420862.2019.1618674. Epub 2019 Jun 4.
• [6] Association between genetic variants of mast-cell chymase and eczema.Lancet. 1996 Aug 31;348(9027):581-3. doi: 10.1016/s0140-6736(95)10244-2.
• [7] Risk of breast cancer and residential proximity to industrial installations: New findings from a multicase-control study (MCC-Spain).Environ Pollut. 2018 Jun;237:559-568. doi: 10.1016/j.envpol.2018.02.065. Epub 2018 Mar 15.
• [8] Loss of heterozygosity of APC/MCC gene in differentiated and undifferentiated gastric carcinomas in Taiwan.Cancer Lett. 1995 Sep 25;96(2):169-74. doi: 10.1016/0304-3835(95)03925-m.
• [9] Duplication of two distinct regions on chromosome 5q in non-papillary renal-cell carcinomas.Int J Cancer. 1998 May 4;76(3):337-40. doi: 10.1002/(sici)1097-0215(19980504)76:3<337::aid-ijc9>3.0.co;2-w.
• [10] Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair.Clin Chem. 2017 Mar;63(3):700-713. doi: 10.1373/clinchem.2016.263582. Epub 2016 Dec 22.
• [11] Therapeutic Suppression of miR-4261 Attenuates Colorectal Cancer by Targeting MCC.Mol Ther Nucleic Acids. 2017 Sep 15;8:36-45. doi: 10.1016/j.omtn.2017.05.010. Epub 2017 Jun 1.
• [12] Tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division.Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):E954-E963. doi: 10.1073/pnas.1712052115. Epub 2018 Jan 18.
• [13] High adherence to the Western, Prudent, and Mediterranean dietary patterns and risk of gastric adenocarcinoma: MCC-Spain study.Gastric Cancer. 2018 May;21(3):372-382. doi: 10.1007/s10120-017-0774-x. Epub 2017 Nov 14.
• [14] Novel nucleoside analogue MCC-478 (LY582563) is effective against wild-type or lamivudine-resistant hepatitis B virus.Antimicrob Agents Chemother. 2002 Aug;46(8):2602-5. doi: 10.1128/AAC.46.8.2602-2605.2002.
• [15] Absence of APC gene mutation in the mutation cluster region in hepatocellular carcinoma.Cancer Lett. 1998 Dec 11;134(1):23-8. doi: 10.1016/s0304-3835(98)00238-9.
• [16] Mutated in colorectal cancer protein modulates the NFB pathway.Anticancer Res. 2012 Jan;32(1):73-9.
• [17] MCC-555-induced NAG-1 expression is mediated in part by KLF4.Eur J Pharmacol. 2010 Jul 10;637(1-3):30-7. doi: 10.1016/j.ejphar.2010.03.055. Epub 2010 Apr 10.
• [18] The putative tumor suppressor gene on chromosome 5q for hepatocellular carcinoma is distinct from the MCC and APC genes.Cancer Detect Prev. 1993;17(3):405-9.
• [19] MCC, a candidate familial polyposis gene in 5q.21, shows frequent allele loss in colorectal and lung cancer.Oncogene. 1991 Oct;6(10):1881-6.
• [20] Malignant blue nevus: a case report and molecular analysis.Am J Dermatopathol. 2003 Feb;25(1):21-7. doi: 10.1097/00000372-200302000-00005.
• [21] CEACAM1 mediates B cell aggregation in central nervous system autoimmunity.Sci Rep. 2016 Jul 20;6:29847. doi: 10.1038/srep29847.
• [22] Activation of the Intrinsic Pain Inhibitory Circuit from the Midcingulate Cg2 to Zona Incerta Alleviates Neuropathic Pain.J Neurosci. 2019 Nov 13;39(46):9130-9144. doi: 10.1523/JNEUROSCI.1683-19.2019. Epub 2019 Oct 11.
• [23] An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.Diabetes. 2017 Nov;66(11):2888-2902. doi: 10.2337/db16-1253. Epub 2017 May 31.
• [24] A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4. Toxicol Appl Pharmacol. 2012 Sep 1;263(2):225-32. doi: 10.1016/j.taap.2012.06.014. Epub 2012 Jun 30.
• [25] Evaluating the Association between Artificial Light-at-Night Exposure and Breast and Prostate Cancer Risk in Spain (MCC-Spain Study).Environ Health Perspect. 2018 Apr 23;126(4):047011. doi: 10.1289/EHP1837.
• [26] Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia.Sci Rep. 2016 May 26;6:26688. doi: 10.1038/srep26688.
• [27] Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients.J Hum Genet. 2011 Apr;56(4):316-23. doi: 10.1038/jhg.2011.12. Epub 2011 Feb 17.
• [28] Polymorphic sites within the MCC and APC loci reveal very frequent loss of heterozygosity in human small cell lung cancer.Cancer Res. 1992 Apr 1;52(7):1996-9.
• [29] Impact of novel polymorphisms related to cytotoxicity of cytarabine in the induction treatment of acute myeloid leukemia.Pharmacogenet Genomics. 2017 Jul;27(7):270-274. doi: 10.1097/FPC.0000000000000286.
• [30] Adenomatous polyposis coli and a cytogenetic deletion of chromosome 5 resulting from a maternal intrachromosomal insertion.J Med Genet. 1994 Apr;31(4):312-6. doi: 10.1136/jmg.31.4.312.
• [31] Flavonoids and the Risk of Gastric Cancer: An Exploratory Case-Control Study in the MCC-Spain Study.Nutrients. 2019 Apr 27;11(5):967. doi: 10.3390/nu11050967.
• [32] Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers.Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3385-8. doi: 10.1073/pnas.89.8.3385.
• [33] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [34] LOH at the APC/MCC gene (5Q21) is frequent in early stages of non-small cell lung cancer.Pathol Res Pract. 1999;195(10):677-80. doi: 10.1016/S0344-0338(99)80058-2.
• [35] Loss of heterozygosity at APC and MCC genes of oral cancer and leukoplakia tissues from Indian tobacco chewers.J Oral Pathol Med. 2003 Sep;32(8):450-4. doi: 10.1034/j.1600-0714.2003.00132.x.
• [36] Adherence to the Western, Prudent, and Mediterranean dietary patterns and chronic lymphocytic leukemia in the MCC-Spain study.Haematologica. 2018 Nov;103(11):1881-1888. doi: 10.3324/haematol.2018.192526. Epub 2018 Jun 28.
• [37] 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.
• [38] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [39] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [40] 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.
• [41] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [42] 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.
• [43] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [44] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [45] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [46] 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.
• [47] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [48] 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.
• [49] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [50] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [51] 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.