Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGZGZ5)

• DOT Name: Axin-1 (AXIN1)
• Synonyms: Axis inhibition protein 1; hAxin
• Gene Name: AXIN1
• Related Disease:
  Estrogen-receptor positive breast cancer
  Liver cirrhosis
  Parkinson disease
  Adenocarcinoma
  Adult glioblastoma
  Adult hepatocellular carcinoma
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Carcinoma
  Cardiovascular disease
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Endometrial carcinoma
  Endometriosis
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Hepatitis B virus infection
  Inflammatory bowel disease
  Liver cancer
  Lung neoplasm
  Medulloblastoma
  Non-small-cell lung cancer
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Brain neoplasm
  Breast carcinoma
  Caudal duplication
  Cervical cancer
  Cervical carcinoma
  Colorectal adenoma
  Familial adenomatous polyposis
  Metastatic malignant neoplasm
  Osteoarthritis
• UniProt ID: AXIN1_HUMAN
• PDB ID: 1DK8; 1EMU; 1O9U; 3ZDI; 4B7T; 4NM0; 4NM3; 4NM5; 4NM7; 4NU1; 5WZZ; 6JCK; 7SXF; 7SXG; 7SXH; 7SXJ
• Pfam ID: PF16646 ; PF08833 ; PF00778 ; PF00615
• Sequence:
  MNIQEQGFPLDLGASFTEDAPRPPVPGEEGELVSTDPRPASYSFCSGKGVGIKGETSTAT
  PRRSDLDLGYEPEGSASPTPPYLKWAESLHSLLDDQDGISLFRTFLKQEGCADLLDFWFA
  CTGFRKLEPCDSNEEKRLKLARAIYRKYILDNNGIVSRQTKPATKSFIKGCIMKQLIDPA
  MFDQAQTEIQATMEENTYPSFLKSDIYLEYTRTGSESPKVCSDQSSGSGTGKGISGYLPT
  LNEDEEWKCDQDMDEDDGRDAAPPGRLPQKLLLETAAPRVSSSRRYSEGREFRYGSWREP
  VNPYYVNAGYALAPATSANDSEQQSLSSDADTLSLTDSSVDGIPPYRIRKQHRREMQESV
  QVNGRVPLPHIPRTYRVPKEVRVEPQKFAEELIHRLEAVQRTREAEEKLEERLKRVRMEE
  EGEDGDPSSGPPGPCHKLPPAPAWHHFPPRCVDMGCAGLRDAHEENPESILDEHVQRVLR
  TPGRQSPGPGHRSPDSGHVAKMPVALGGAASGHGKHVPKSGAKLDAAGLHHHRHVHHHVH
  HSTARPKEQVEAEATRRAQSSFAWGLEPHSHGARSRGYSESVGAAPNASDGLAHSGKVGV
  ACKRNAKKAESGKSASTEVPGASEDAEKNQKIMQWIIEGEKEISRHRRTGHGSSGTRKPQ
  PHENSRPLSLEHPWAGPQLRTSVQPSHLFIQDPTMPPHPAPNPLTQLEEARRRLEEEEKR
  ASRAPSKQRYVQEVMRRGRACVRPACAPVLHVVPAVSDMELSETETRSQRKVGGGSAQPC
  DSIVVAYYFCGEPIPYRTLVRGRAVTLGQFKELLTKKGSYRYYFKKVSDEFDCGVVFEEV
  REDEAVLPVFEEKIIGKVEKVD
• Function: Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling. Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway. In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B. Likely to function as a tumor suppressor. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7. Also a component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Cushing syndrome (hsa04934)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Endometrial cancer (hsa05213)
  Basal cell carcinoma (hsa05217)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  TCF dependent signaling in response to WNT (R-HSA-201681)
  Degradation of AXIN (R-HSA-4641257)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Signaling by GSK3beta mutants (R-HSA-5339716)
  CTNNB1 S33 mutants aren't phosphorylated (R-HSA-5358747)
  CTNNB1 S37 mutants aren't phosphorylated (R-HSA-5358749)
  CTNNB1 S45 mutants aren't phosphorylated (R-HSA-5358751)
  CTNNB1 T41 mutants aren't phosphorylated (R-HSA-5358752)
  APC truncation mutants have impaired AXIN binding (R-HSA-5467337)
  AXIN missense mutants destabilize the destruction complex (R-HSA-5467340)
  Truncations of AMER1 destabilize the destruction complex (R-HSA-5467348)
  Ub-specific processing proteases (R-HSA-5689880)
  RUNX1 regulates estrogen receptor mediated transcription (R-HSA-8931987)
  RUNX1 regulates transcription of genes involved in WNT signaling (R-HSA-8939256)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Estrogen-receptor positive breast cancer	DIS1H502	Definitive	Biomarker	[1]
Liver cirrhosis	DIS4G1GX	Definitive	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Definitive	Altered Expression	[3]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Adult hepatocellular carcinoma	DIS6ZPAI	Strong	Altered Expression	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[9]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[11]
Colon cancer	DISVC52G	Strong	Biomarker	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[13]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[14]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[15]
Endometriosis	DISX1AG8	Strong	Biomarker	[16]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[17]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[17]
Gastric cancer	DISXGOUK	Strong	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[19]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[20]
Liver cancer	DISDE4BI	Strong	Genetic Variation	[21]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[22]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[24]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[24]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[25]
Stomach cancer	DISKIJSX	Strong	Biomarker	[18]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[26]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[27]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[28]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[28]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[29]
Brain neoplasm	DISY3EKS	Limited	Biomarker	[30]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]
Caudal duplication	DISKJHDA	Limited	Autosomal dominant	[31]
Cervical cancer	DISFSHPF	Limited	Biomarker	[32]
Cervical carcinoma	DIST4S00	Limited	Biomarker	[32]
Colorectal adenoma	DISTSVHM	Limited	Autosomal dominant	[33]
Familial adenomatous polyposis	DISW53RE	Limited	Biomarker	[34]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[35]
Osteoarthritis	DIS05URM	Limited	Biomarker	[36]

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 Axin-1 (AXIN1).	[37]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Axin-1 (AXIN1).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Axin-1 (AXIN1).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Axin-1 (AXIN1).	[38]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Axin-1 (AXIN1).	[39]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Axin-1 (AXIN1).	[40]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Axin-1 (AXIN1).	[41]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Axin-1 (AXIN1).	[42]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Axin-1 (AXIN1).	[44]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Axin-1 (AXIN1).	[39]
Daporinad	DMCU74R	Phase 2	Daporinad increases the expression of Axin-1 (AXIN1).	[45]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Axin-1 (AXIN1).	[46]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Axin-1 (AXIN1).	[47]
Calphostin C	DM9X2D0	Terminated	Calphostin C decreases the expression of Axin-1 (AXIN1).	[48]

References

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• [4] Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear beta-catenin expression.Br J Cancer. 2004 Feb 23;90(4):892-9. doi: 10.1038/sj.bjc.6601589.
• [5] Microtubule actin cross-linking factor 1, a novel target in glioblastoma.Int J Oncol. 2017 Jan;50(1):310-316. doi: 10.3892/ijo.2016.3798. Epub 2016 Dec 9.
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• [8] Down-regulation of microRNA-31-5p inhibits proliferation and invasion of osteosarcoma cells through Wnt/-catenin signaling pathway by enhancing AXIN1.Exp Mol Pathol. 2019 Jun;108:32-41. doi: 10.1016/j.yexmp.2019.03.001. Epub 2019 Mar 4.
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• [10] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
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• [16] AXIN1 in Plasma or Serum Is a Potential New Biomarker for Endometriosis.Int J Mol Sci. 2019 Jan 7;20(1):189. doi: 10.3390/ijms20010189.
• [17] Aberrant nuclear localization of beta-catenin without genetic alterations in beta-catenin or Axin genes in esophageal cancer.World J Surg Oncol. 2007 Feb 19;5:21. doi: 10.1186/1477-7819-5-21.
• [18] Mutations in components of the Wnt signaling pathway in gastric cancer.World J Gastroenterol. 2008 Mar 14;14(10):1570-4. doi: 10.3748/wjg.14.1570.
• [19] Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015 May;47(5):505-511. doi: 10.1038/ng.3252. Epub 2015 Mar 30.
• [20] Vitamin D receptor is a novel transcriptional regulator for Axin1.J Steroid Biochem Mol Biol. 2017 Jan;165(Pt B):430-437. doi: 10.1016/j.jsbmb.2016.09.002. Epub 2016 Sep 4.
• [21] AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of -catenin activation.J Hepatol. 2018 Jun;68(6):1203-1213. doi: 10.1016/j.jhep.2017.12.018. Epub 2018 Mar 7.
• [22] Overexpression of axin downregulates TCF-4 and inhibits the development of lung cancer.Ann Surg Oncol. 2007 Nov;14(11):3251-9. doi: 10.1245/s10434-007-9555-9. Epub 2007 Sep 1.
• [23] No evidence for mutations or altered expression of the Suppressor of Fused gene (SUFU) in primitive neuroectodermal tumours.Neuropathol Appl Neurobiol. 2004 Oct;30(5):532-9. doi: 10.1111/j.1365-2990.2004.00560.x.
• [24] Mutations in the AXIN1 gene in advanced prostate cancer.Eur Urol. 2009 Sep;56(3):486-94. doi: 10.1016/j.eururo.2008.05.029. Epub 2008 May 23.
• [25] Frequent genetic alterations and reduced expression of the Axin1 gene in oral squamous cell carcinoma: involvement in tumor progression and metastasis.Oncol Rep. 2007 Jan;17(1):73-9.
• [26] Tankyrase as a Novel Molecular Target in Cancer and Fibrotic Diseases.Curr Drug Targets. 2017;18(10):1214-1224. doi: 10.2174/1389450117666160715152503.
• [27] RIF1 promotes tumor growth and cancer stem cell-like traits in NSCLC by protein phosphatase 1-mediated activation of Wnt/-catenin signaling.Cell Death Dis. 2018 Sep 20;9(10):942. doi: 10.1038/s41419-018-0972-4.
• [28] Typing tumors using pathways selected by somatic evolution.Nat Commun. 2018 Oct 8;9(1):4159. doi: 10.1038/s41467-018-06464-y.
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• [30] AXIN1 Expression and Localization in Meningiomas and Association to Changes of APC and E-cadherin.Anticancer Res. 2016 Sep;36(9):4583-94. doi: 10.21873/anticanres.11007.
• [31] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
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• [33] 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.
• [34] Manilkara zapota (L.) P. Royen leaf water extract triggered apoptosis and activated caspase-dependent pathway in HT-29 human colorectal cancer cell line.Biomed Pharmacother. 2019 Feb;110:748-757. doi: 10.1016/j.biopha.2018.12.027. Epub 2018 Dec 13.
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• [36] Deletion of Axin1 in condylar chondrocytes leads to osteoarthritis-like phenotype in temporomandibular joint via activation of -catenin and FGF signaling.J Cell Physiol. 2019 Feb;234(2):1720-1729. doi: 10.1002/jcp.27043. Epub 2018 Aug 2.
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• [38] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [39] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [40] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [41] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [42] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
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• [46] BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells. Stem Cell Res Ther. 2016 Feb 1;7:22. doi: 10.1186/s13287-016-0278-3.
• [47] 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.
• [48] Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
• [49] 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.