Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCG4TSY)

DOT Name	Homeobox protein CDX-2 (CDX2)
Synonyms	CDX-3; Caudal-type homeobox protein 2
Gene Name	CDX2
Related Disease	Colon polyp ( ) Pancreatic cancer ( ) Acute leukaemia ( ) Adenoma ( ) Autism spectrum disorder ( ) Cholangiocarcinoma ( ) Colonic neoplasm ( ) Esophageal adenocarcinoma ( ) Esophagitis ( ) Familial adenomatous polyposis ( ) Gallbladder cancer ( ) Gastric adenocarcinoma ( ) Gastric neoplasm ( ) Gastritis ( ) Gastroesophageal reflux disease ( ) Hamartoma ( ) Hepatocellular carcinoma ( ) Lung adenocarcinoma ( ) Matthew-Wood syndrome ( ) Mucinous adenocarcinoma ( ) Non-small-cell lung cancer ( ) Osteoporosis ( ) Pancreatic ductal carcinoma ( ) Precancerous condition ( ) Squamous cell carcinoma ( ) Tuberculosis ( ) Ulcerative colitis ( ) Colon adenocarcinoma ( ) Gastric cancer ( ) Intrahepatic cholangiocarcinoma ( ) Neuroendocrine neoplasm ( ) Skin cancer ( ) Teratoma ( ) Childhood acute lymphoblastic leukemia ( ) Acute myelogenous leukaemia ( ) Carcinoma ( ) Endometrial carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Melanoma ( ) Pancreatic adenocarcinoma ( ) Pulmonary tuberculosis ( )
UniProt ID	CDX2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5LTY; 6ES2; 6ES3; 7Q4N
Pfam ID	PF04731 ; PF00046
Sequence	MYVSYLLDKDVSMYPSSVRHSGGLNLAPQNFVSPPQYPDYGGYHVAAAAAAAANLDSAQS PGPSWPAAYGAPLREDWNGYAPGGAAAAANAVAHGLNGGSPAAAMGYSSPADYHPHHHPH HHPHHPAAAPSCASGLLQTLNPGPPGPAATAAAEQLSPGGQRRNLCEWMRKPAQQSLGSQ VKTRTKDKYRVVYTDHQRLELEKEFHYSRYITIRRKAELAATLGLSERQVKIWFQNRRAK ERKINKKKLQQQQQQQPPQPPPPPPQPPQPQPGPLRSVPEPLSPVSSLQASVPGSVPGVL GPTGGVLNPTVTQ
Function	Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium. Binds to the promoter of the intestinal sucrase-isomaltase SI and activates SI transcription. Binds to the DNA sequence 5'-ATAAAAACTTAT-3' in the promoter region of VDR and activates VDR transcription. Binds to and activates transcription of LPH. Activates transcription of CLDN2 and intestinal mucin MUC2. Binds to the 5'-AATTTTTTACAACACCT-3' DNA sequence in the promoter region of CA1 and activates CA1 transcription. Important in broad range of functions from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine. Binds preferentially to methylated DNA.
Tissue Specificity	Detected in small intestine, colon and pancreas.
KEGG Pathway	Gastric cancer (hsa05226 )
Reactome Pathway	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771 )

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Colon polyp	DIS7V594	Definitive	Altered Expression	[1]
Pancreatic cancer	DISJC981	Definitive	Altered Expression	[2]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[3]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[7]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[8]
Esophagitis	DISHVC9B	Strong	Altered Expression	[9]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[10]
Gallbladder cancer	DISXJUAF	Strong	Genetic Variation	[6]
Gastric adenocarcinoma	DISWWLTC	Strong	Altered Expression	[11]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[12]
Gastritis	DIS8G07K	Strong	Biomarker	[11]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[13]
Hamartoma	DIS0I87H	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[16]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[17]
Mucinous adenocarcinoma	DISKNFE8	Strong	Altered Expression	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[16]
Osteoporosis	DISF2JE0	Strong	Biomarker	[19]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Altered Expression	[20]
Precancerous condition	DISV06FL	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[21]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[19]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[22]
Colon adenocarcinoma	DISDRE0J	moderate	Biomarker	[23]
Gastric cancer	DISXGOUK	moderate	Biomarker	[24]
Intrahepatic cholangiocarcinoma	DIS6GOC8	moderate	Biomarker	[25]
Neuroendocrine neoplasm	DISNPLOO	moderate	Biomarker	[26]
Skin cancer	DISTM18U	moderate	Biomarker	[27]
Teratoma	DIS6ICY4	moderate	Biomarker	[23]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Disputed	Altered Expression	[28]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[29]
Carcinoma	DISH9F1N	Limited	Biomarker	[30]
Endometrial carcinoma	DISXR5CY	Limited	Biomarker	[31]
Lung cancer	DISCM4YA	Limited	Biomarker	[32]
Lung carcinoma	DISTR26C	Limited	Biomarker	[32]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[33]
Pancreatic adenocarcinoma	DISKHX7S	Limited	Biomarker	[2]
Pulmonary tuberculosis	DIS6FLUM	Limited	Genetic Variation	[34]
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⏷ Show the Full List of 42 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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 Homeobox protein CDX-2 (CDX2).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein CDX-2 (CDX2).	[41]
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8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein CDX-2 (CDX2).	[36]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein CDX-2 (CDX2).	[37]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein CDX-2 (CDX2).	[38]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Homeobox protein CDX-2 (CDX2).	[39]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Homeobox protein CDX-2 (CDX2).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Homeobox protein CDX-2 (CDX2).	[42]
SB-431542	DM0YOXQ	Preclinical	SB-431542 affects the expression of Homeobox protein CDX-2 (CDX2).	[43]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the expression of Homeobox protein CDX-2 (CDX2).	[44]
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⏷ Show the Full List of 8 Drug(s)

References

1	Suppression of colonic polyposis by homeoprotein CDX2 through its nontranscriptional function that stabilizes p27Kip1.Cancer Res. 2011 Jan 15;71(2):593-602. doi: 10.1158/0008-5472.CAN-10-2842. Epub 2011 Jan 11.
2	CDX2 inhibits pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p.Tumour Biol. 2016 Jan;37(1):1041-9. doi: 10.1007/s13277-015-3900-6. Epub 2015 Aug 14.
3	Cdx2 homeoprotein inhibits non-homologous end joining in colon cancer but not in leukemia cells.Nucleic Acids Res. 2012 Apr;40(8):3456-69. doi: 10.1093/nar/gkr1242. Epub 2011 Dec 20.
4	Single-cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence.Int J Cancer. 2019 Apr 1;144(7):1561-1573. doi: 10.1002/ijc.31869. Epub 2018 Dec 11.
5	Polymorphisms in Vitamin D Receptor Genes in Association with Childhood Autism Spectrum Disorder.Dis Markers. 2018 Jan 11;2018:7862892. doi: 10.1155/2018/7862892. eCollection 2018.
6	Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma.J Cancer Res Clin Oncol. 2006 Dec;132(12):805-10. doi: 10.1007/s00432-006-0129-1. Epub 2006 Jun 23.
7	The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanisms.J Exp Med. 2018 Mar 5;215(3):911-926. doi: 10.1084/jem.20170934. Epub 2018 Feb 8.
8	Barrett's esophagus: cancer and molecular biology.Ann N Y Acad Sci. 2013 Oct;1300:296-314. doi: 10.1111/nyas.12252.
9	Regulation of CDX2 expression in esophageal adenocarcinoma.Mol Carcinog. 2009 Oct;48(10):965-74. doi: 10.1002/mc.20549.
10	Development and Characterization of a Genetic Mouse Model of KRAS Mutated Colorectal Cancer.Int J Mol Sci. 2019 Nov 13;20(22):5677. doi: 10.3390/ijms20225677.
11	Activation of FXR promotes intestinal metaplasia of gastric cells via SHP-dependent upregulation of the expression of CDX2.Oncol Lett. 2018 May;15(5):7617-7624. doi: 10.3892/ol.2018.8342. Epub 2018 Mar 23.
12	Nuclear transcription factor CDX2 inhibits gastric cancercell growth and reverses epithelialtomesenchymal transition in vitro and in vivo.Mol Med Rep. 2015 Oct;12(4):5231-8. doi: 10.3892/mmr.2015.4114. Epub 2015 Jul 22.
13	CDX-2 Expression in Esophageal Biopsies Without Goblet Cell Intestinal Metaplasia May Be Predictive of Barrett's Esophagus.Dig Dis Sci. 2020 Jul;65(7):1992-1998. doi: 10.1007/s10620-019-05914-x. Epub 2019 Nov 5.
14	Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer.Int J Cancer. 2007 Sep 15;121(6):1219-26. doi: 10.1002/ijc.22828.
15	Aberrant CDX2 expression in hepatocellular carcinomas: an important diagnostic pitfall.Hum Pathol. 2017 Jun;64:13-18. doi: 10.1016/j.humpath.2016.12.029. Epub 2017 Jan 13.
16	Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.Clin Cancer Res. 2018 Sep 1;24(17):4089-4097. doi: 10.1158/1078-0432.CCR-18-0483. Epub 2018 Jul 17.
17	Immunohistochemical profiling of liver metastases and matched-pair analysis in patients with metastatic pancreatic ductal adenocarcinoma.Pancreatology. 2019 Oct;19(7):963-970. doi: 10.1016/j.pan.2019.09.005. Epub 2019 Sep 14.
18	Establishment and characterization of a murine xenograft model of appendiceal mucinous adenocarcinoma.Int J Exp Pathol. 2010 Aug;91(4):357-67. doi: 10.1111/j.1365-2613.2010.00721.x. Epub 2010 Jun 25.
19	Cdx-2 polymorphism in the vitamin D receptor gene (VDR) marks VDR expression in monocyte/macrophages through VDR promoter methylation.Immunogenetics. 2018 Aug;70(8):523-532. doi: 10.1007/s00251-018-1063-5. Epub 2018 May 28.
20	Utilization of CDX2 expression in diagnosing pancreatic ductal adenocarcinoma and predicting prognosis.PLoS One. 2014 Jan 29;9(1):e86853. doi: 10.1371/journal.pone.0086853. eCollection 2014.
21	Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis?.J Clin Pathol. 2013 Feb;66(2):109-12. doi: 10.1136/jclinpath-2012-201138. Epub 2012 Oct 26.
22	Caudal type homeobox 2 expression induced by leukocytapheresis might be associated with mucosal healing in ulcerative colitis.J Gastroenterol Hepatol. 2017 May;32(5):1032-1039. doi: 10.1111/jgh.13645.
23	Caudal Homeobox Gene-2 Staining Defines Intracranial Mature Teratoma with Differentiation to Colonic Adenocarcinoma.World Neurosurg. 2019 Dec;132:239-244. doi: 10.1016/j.wneu.2019.08.216. Epub 2019 Sep 11.
24	Targeting claudin-4 enhances CDDP-chemosensitivity in gastric cancer.Oncotarget. 2019 Mar 15;10(22):2189-2202. doi: 10.18632/oncotarget.26758. eCollection 2019 Mar 15.
25	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.
26	Neuroendocrine Liver Metastasis-a Specific Set of Markers to Detect Primary Tumor Sites.Endocr Pathol. 2019 Mar;30(1):31-34. doi: 10.1007/s12022-018-9558-z.
27	Vitamin D receptor polymorphisms and cancer.Adv Exp Med Biol. 2014;810:69-105. doi: 10.1007/978-1-4939-0437-2_5.
28	Aberrant expression of the homeobox gene CDX2 in pediatric acute lymphoblastic leukemia.Blood. 2009 Apr 23;113(17):4049-51. doi: 10.1182/blood-2008-12-196634. Epub 2009 Feb 13.
29	The microRNA miR-196b acts as a tumor suppressor in Cdx2-driven acute myeloid leukemia.Haematologica. 2020 Jun;105(6):e285-e289. doi: 10.3324/haematol.2019.223297. Epub 2019 Sep 26.
30	SATB2 Is Superior to CDX2 in Distinguishing Signet Ring Cell Carcinoma of the Upper Gastrointestinal Tract and Lower Gastrointestinal Tract.Am J Surg Pathol. 2018 Dec;42(12):1715-1722. doi: 10.1097/PAS.0000000000001159.
31	Intestinal differentiated mucinous adenocarcinoma of the endometrium with sporadic MSI high status: a case report.Diagn Pathol. 2017 May 12;12(1):39. doi: 10.1186/s13000-017-0629-0.
32	Immunohistochemical profiles in primary lung cancers and epithelial pulmonary metastases.Hum Pathol. 2019 Feb;84:221-230. doi: 10.1016/j.humpath.2018.10.009. Epub 2018 Oct 31.
33	Vitamin D receptor polymorphisms and melanoma.Oncol Lett. 2019 May;17(5):4162-4169. doi: 10.3892/ol.2018.9733. Epub 2018 Nov 19.
34	Influence of Cdx2 and TaqI Gene Variants on Vitamin D(3) Modulated Intracellular Chemokine Positive T-Cell Subsets in Pulmonary Tuberculosis.Clin Ther. 2017 May;39(5):946-957. doi: 10.1016/j.clinthera.2017.04.003. Epub 2017 May 2.
35	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.
36	Effect of chronic exposure to inorganic arsenic on intestinal cells. J Appl Toxicol. 2019 Jun;39(6):899-907. doi: 10.1002/jat.3778. Epub 2019 Feb 12.
37	Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
38	Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis. 2007 Feb;28(2):488-96. doi: 10.1093/carcin/bgl176. Epub 2006 Sep 21.
39	Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
40	Inflammatory mediators of esophagitis alter p27 Kip1 expression in esophageal epithelial cells. J Pediatr Gastroenterol Nutr. 2010 Nov;51(5):556-62. doi: 10.1097/MPG.0b013e3181ecd65d.
41	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.
42	CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
43	Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
44	Oxyresveratrol improves tight junction integrity through the PKC and MAPK signaling pathways in Caco-2?cells. Food Chem Toxicol. 2017 Oct;108(Pt A):203-213. doi: 10.1016/j.fct.2017.08.002. Epub 2017 Aug 2.