Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1WZ2QO)

DOT Name	Tomoregulin-2 (TMEFF2)
Synonyms	TR-2; Hyperplastic polyposis protein 1; Transmembrane protein with EGF-like and two follistatin-like domains
Gene Name	TMEFF2
Related Disease	Esophageal squamous cell carcinoma ( ) Advanced cancer ( ) Alzheimer disease ( ) Barrett esophagus ( ) Bladder cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Colorectal neoplasm ( ) Ductal breast carcinoma in situ ( ) Endometrial cancer ( ) Endometrial carcinoma ( ) Familial adenomatous polyposis ( ) Gastric cancer ( ) Gastric neoplasm ( ) Inflammatory bowel disease ( ) Lung cancer ( ) Lung carcinoma ( ) Neoplasm ( ) Neoplasm of esophagus ( ) Non-alcoholic fatty liver disease ( ) Non-small-cell lung cancer ( ) Oral cancer ( ) Persistent truncus arteriosus ( ) Polycystic ovarian syndrome ( ) Prostate cancer ( ) Renal cell carcinoma ( ) Stomach cancer ( ) Type-1/2 diabetes ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Pancreatic cancer ( ) Adenocarcinoma ( ) Androgen insensitivity syndrome ( ) Prostate carcinoma ( ) Prostate neoplasm ( )
UniProt ID	TEFF2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF07648
Sequence	MVLWESPRQCSSWTLCEGFCWLLLLPVMLLIVARPVKLAAFPTSLSDCQTPTGWNCSGYD DRENDLFLCDTNTCKFDGECLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQAA CKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKETSTCDICQFGAECDEDAEDVWC VCNIDCSQTNFNPLCASDGKSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSEDG HYARTDYAENANKLEESAREHHIPCPEHYNGFCMHGKCEHSINMQEPSCRCDAGYTGQHC EKKDYSVLYVVPGPVRFQYVLIAAVIGTIQIAVICVVVLCITRKCPRSNRIHRQKQNTGH YSSDNTTRASTRLI
Function	May be a survival factor for hippocampal and mesencephalic neurons. The shedded form up-regulates cancer cell proliferation, probably by promoting ERK1/2 phosphorylation.
Tissue Specificity	Highly expressed in adult and fetal brain, spinal cord and prostate. Expressed in all brain regions except the pituitary gland, with highest levels in amygdala and corpus callosum. Expressed in the pericryptal myofibroblasts and other stromal cells of normal colonic mucosa. Expressed in prostate carcinoma. Down-regulated in colorectal cancer. Present in Alzheimer disease plaques (at protein level). Isoform 3 is expressed weakly in testis and at high levels in normal and cancerous prostate.

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Barrett esophagus	DIS416Y7	Strong	Posttranslational Modification	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Posttranslational Modification	[7]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[8]
Colon carcinoma	DISJYKUO	Strong	Posttranslational Modification	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Colorectal neoplasm	DISR1UCN	Strong	Posttranslational Modification	[10]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[11]
Endometrial cancer	DISW0LMR	Strong	Posttranslational Modification	[12]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[13]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[14]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[15]
Gastric neoplasm	DISOKN4Y	Strong	Posttranslational Modification	[16]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[17]
Lung carcinoma	DISTR26C	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Neoplasm of esophagus	DISOLKAQ	Strong	Posttranslational Modification	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[17]
Oral cancer	DISLD42D	Strong	Biomarker	[19]
Persistent truncus arteriosus	DISRZ8EA	Strong	Biomarker	[20]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[21]
Prostate cancer	DISF190Y	Strong	Biomarker	[22]
Renal cell carcinoma	DISQZ2X8	Strong	Posttranslational Modification	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[15]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[23]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[24]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[24]
Pancreatic cancer	DISJC981	moderate	Biomarker	[25]
Adenocarcinoma	DIS3IHTY	Limited	Posttranslational Modification	[26]
Androgen insensitivity syndrome	DISUZBBO	Limited	Posttranslational Modification	[27]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[22]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[22]
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⏷ Show the Full List of 39 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tomoregulin-2 (TMEFF2).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tomoregulin-2 (TMEFF2).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tomoregulin-2 (TMEFF2).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tomoregulin-2 (TMEFF2).	[32]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tomoregulin-2 (TMEFF2).	[28]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Tomoregulin-2 (TMEFF2).	[33]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Tomoregulin-2 (TMEFF2).	[34]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Tomoregulin-2 (TMEFF2).	[35]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tomoregulin-2 (TMEFF2).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Tomoregulin-2 (TMEFF2).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Tomoregulin-2 (TMEFF2).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tomoregulin-2 (TMEFF2).	[40]
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⏷ Show the Full List of 12 Drug(s)

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tomoregulin-2 (TMEFF2).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tomoregulin-2 (TMEFF2).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tomoregulin-2 (TMEFF2).	[39]
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References

1	Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma.Oncol Rep. 2009 Apr;21(4):1067-73. doi: 10.3892/or_00000325.
2	Novel methylation panel for the early detection of neoplasia in high-risk ulcerative colitis and Crohn's colitis patients.Inflamm Bowel Dis. 2013 Jan;19(1):165-73. doi: 10.1002/ibd.22994.
3	Tomoregulin-2 is found extensively in plaques in Alzheimer's disease brain.J Neurochem. 2006 Jul;98(1):34-44. doi: 10.1111/j.1471-4159.2006.03801.x.
4	Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk.Oncogene. 2005 Jun 9;24(25):4138-48. doi: 10.1038/sj.onc.1208598.
5	Detection of urothelial carcinoma, upper tract urothelial carcinoma, bladder carcinoma, and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective, single-center study.Urol Oncol. 2018 Jul;36(7):342.e15-342.e23. doi: 10.1016/j.urolonc.2018.04.001. Epub 2018 Apr 26.
6	Validation of DNA promoter hypermethylation biomarkers in breast cancer--a short report.Cell Oncol (Dordr). 2014 Aug;37(4):297-303. doi: 10.1007/s13402-014-0189-1. Epub 2014 Aug 16.
7	The effect of TMEFF2 methylation on the tumor stage and survival outcome of clear cell renal cell carcinoma.Cancer Biomark. 2017;19(2):207-212. doi: 10.3233/CBM-161656.
8	The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer.Cancer Biol Ther. 2014 Sep;15(9):1198-207. doi: 10.4161/cbt.29500. Epub 2014 Jun 11.
9	Frameshift mutation of candidate tumor suppressor genes QK1 and TMEFF2 in gastric and colorectal cancers.Cancer Biomark. 2019;24(1):1-6. doi: 10.3233/CBM-160559.
10	Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions.World J Gastroenterol. 2007 Feb 14;13(6):950-4. doi: 10.3748/wjg.v13.i6.950.
11	Promoter CpG island hypermethylation during breast cancer progression.Virchows Arch. 2011 Jan;458(1):73-84. doi: 10.1007/s00428-010-1013-6. Epub 2010 Dec 1.
12	Quantitative DNA methylation analysis of selected genes in endometrial carcinogenesis.Taiwan J Obstet Gynecol. 2015 Oct;54(5):572-9. doi: 10.1016/j.tjog.2015.08.010.
13	TMEFF2 is a novel prognosis signature and target for endometrial carcinoma.Life Sci. 2020 Feb 15;243:116910. doi: 10.1016/j.lfs.2019.116910. Epub 2019 Oct 11.
14	Relation between normal rectal methylation, smoking status, and the presence or absence of colorectal adenomas.Cancer. 2010 Oct 1;116(19):4495-501. doi: 10.1002/cncr.25348.
15	TMEFF2 deregulation contributes to gastric carcinogenesis and indicates poor survival outcome.Clin Cancer Res. 2014 Sep 1;20(17):4689-704. doi: 10.1158/1078-0432.CCR-14-0315. Epub 2014 Jul 1.
16	Distinct TPEF/HPP1 gene methylation patterns in gastric cancer indicate a field effect in gastric carcinogenesis.Dig Liver Dis. 2008 Dec;40(12):920-6. doi: 10.1016/j.dld.2008.05.004. Epub 2008 Sep 16.
17	Methylation of TMEFF2 gene in tissue and serum DNA from patients with non-small cell lung cancer.Mol Cells. 2012 Aug;34(2):171-6. doi: 10.1007/s10059-012-0083-5. Epub 2012 Jul 18.
18	qFIBS: An Automated Technique for Quantitative Evaluation of Fibrosis, Inflammation, Ballooning, and Steatosis in Patients With Nonalcoholic Steatohepatitis.Hepatology. 2020 Jun;71(6):1953-1966. doi: 10.1002/hep.30986. Epub 2020 May 7.
19	Aberrant DNA methylation of tumor-related genes in oral rinse: a noninvasive method for detection of oral squamous cell carcinoma.Cancer. 2012 Sep 1;118(17):4298-308. doi: 10.1002/cncr.27417. Epub 2012 Jan 17.
20	Methylation of the TPEF- and PAX6-promoters is increased in early bladder cancer and in normal mucosa adjacent to pTa tumours.BJU Int. 2008 Mar;101(6):753-7. doi: 10.1111/j.1464-410X.2007.07322.x. Epub 2007 Dec 7.
21	Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
22	Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer.Oncotarget. 2019 Oct 22;10(58):6234-6244. doi: 10.18632/oncotarget.27263. eCollection 2019 Oct 22.
23	Genome-wide association with diabetes-related traits in the Framingham Heart Study.BMC Med Genet. 2007 Sep 19;8 Suppl 1(Suppl 1):S16. doi: 10.1186/1471-2350-8-S1-S16.
24	Accurate detection of upper tract urothelial carcinoma in tissue and urine by means of quantitative GDF15, TMEFF2 and VIM promoter methylation.Eur J Cancer. 2014 Jan;50(1):226-33. doi: 10.1016/j.ejca.2013.08.025. Epub 2013 Oct 4.
25	Expression of TMEFF2 in Human Pancreatic Cancer Tissue and the Effects of TMEFF2 Knockdown on Cell, Proliferation, and Apoptosis in Human Pancreatic Cell Lines.Med Sci Monit. 2019 May 2;25:3238-3246. doi: 10.12659/MSM.913974.
26	Hypermethylation of hMLH1, HPP1, p14(ARF), p16(INK4A) and APC in primary adenocarcinomas of the small bowel.Int J Cancer. 2006 Sep 15;119(6):1298-302. doi: 10.1002/ijc.21990.
27	DNA methylation profile during multistage progression of pulmonary adenocarcinomas.Virchows Arch. 2011 Aug;459(2):201-11. doi: 10.1007/s00428-011-1079-9. Epub 2011 Apr 15.
28	Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
29	Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
30	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.
31	Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
32	Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
33	Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
34	Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
35	Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
36	Androgen signaling promotes translation of TMEFF2 in prostate cancer cells via phosphorylation of the subunit of the translation initiation factor 2. PLoS One. 2013;8(2):e55257. doi: 10.1371/journal.pone.0055257. Epub 2013 Feb 6.
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	Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
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.
40	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.