Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY8Z9UF)

• DOT Name: Protein TMEPAI (PMEPA1)
• Synonyms: Prostate transmembrane protein androgen induced 1; Solid tumor-associated 1 protein; Transmembrane prostate androgen-induced protein
• Gene Name: PMEPA1
• Related Disease:
  Adenoma
  Adult glioblastoma
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Metastatic prostate carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate neoplasm
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  Gastric cancer
  Stomach cancer
• UniProt ID: PMEPA_HUMAN
• Sequence:
  MHRLMGVNSTAAAAAGQPNVSCTCNCKRSLFQSMEITELEFVQIIIIVVVMMVMVVVITC
  LLSHYKLSARSFISRHSQGRRREDALSSEGCLWPSESTVSGNGIPEPQVYAPPRPTDRLA
  VPPFAQRERFHRFQPTYPYLQHEIDLPPTISLSDGEEPPPYQGPCTLQLRDPEQQLELNR
  ESVRAPPNRTIFDSDLMDSARLGGPCPPSSNSGISATCYGSGGRMEGPPPTYSEVIGHYP
  GSSFQHQQSSGPPSLLEGTRLHHTHIAPLESAAIWSKEKDKQKGHPL
• Function: Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA recruits the intracellular signal transducer and transcriptional modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by the receptor, SMAD2 and SMAD3 then form a heteromeric complex with SMAD4 that translocates to the nucleus to regulate transcription. Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal. Also involved in down-regulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR, probably by recruiting NEDD4.
• Tissue Specificity: Highest expression in prostate. Also expressed in ovary.
• Reactome Pathway: Downregulation of TGF-beta receptor signaling (R-HSA-2173788)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
leukaemia	DISS7D1V	Strong	Altered Expression	[10]
Leukemia	DISNAKFL	Strong	Altered Expression	[10]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[11]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[13]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[9]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[9]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[15]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[16]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[17]
Prostate cancer	DISF190Y	Disputed	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[16]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[18]
Gastric cancer	DISXGOUK	Limited	Biomarker	[19]
Stomach cancer	DISKIJSX	Limited	Biomarker	[19]

31 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 Protein TMEPAI (PMEPA1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein TMEPAI (PMEPA1).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein TMEPAI (PMEPA1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein TMEPAI (PMEPA1).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein TMEPAI (PMEPA1).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein TMEPAI (PMEPA1).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein TMEPAI (PMEPA1).	[27]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein TMEPAI (PMEPA1).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein TMEPAI (PMEPA1).	[29]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Protein TMEPAI (PMEPA1).	[30]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein TMEPAI (PMEPA1).	[31]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein TMEPAI (PMEPA1).	[32]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein TMEPAI (PMEPA1).	[33]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Protein TMEPAI (PMEPA1).	[34]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Protein TMEPAI (PMEPA1).	[35]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Protein TMEPAI (PMEPA1).	[21]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Protein TMEPAI (PMEPA1).	[36]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Protein TMEPAI (PMEPA1).	[21]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of Protein TMEPAI (PMEPA1).	[21]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of Protein TMEPAI (PMEPA1).	[37]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein TMEPAI (PMEPA1).	[38]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein TMEPAI (PMEPA1).	[33]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Protein TMEPAI (PMEPA1).	[39]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Protein TMEPAI (PMEPA1).	[40]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Protein TMEPAI (PMEPA1).	[41]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Protein TMEPAI (PMEPA1).	[42]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein TMEPAI (PMEPA1).	[44]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein TMEPAI (PMEPA1).	[46]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein TMEPAI (PMEPA1).	[47]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Protein TMEPAI (PMEPA1).	[48]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Protein TMEPAI (PMEPA1).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Protein TMEPAI (PMEPA1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein TMEPAI (PMEPA1).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein TMEPAI (PMEPA1).	[45]

References

• [1] Genomic profiling of rectal adenoma and carcinoma by array-based comparative genomic hybridization.BMC Med Genomics. 2012 Nov 16;5:52. doi: 10.1186/1755-8794-5-52.
• [2] PMEPA1 isoform a drives progression of glioblastoma by promoting protein degradation of the Hippo pathway kinase LATS1.Oncogene. 2020 Jan;39(5):1125-1139. doi: 10.1038/s41388-019-1050-9. Epub 2019 Oct 11.
• [3] Prostate--specific G protein couple receptor genes and STAG1/PMEPA1 in peripheral blood from patients with prostatic cancer.Int J Immunopathol Pharmacol. 2006 Oct-Dec;19(4):871-8. doi: 10.1177/039463200601900416.
• [4] PMEPA1/TMEPAI knockout impairs tumour growth and lung metastasis in MDA-MB-231 cells without changing monolayer culture cell growth.J Biochem. 2019 May 1;165(5):411-414. doi: 10.1093/jb/mvz022.
• [5] Transforming growth factor-beta (TGF-beta)-inducible gene TMEPAI converts TGF-beta from a tumor suppressor to a tumor promoter in breast cancer.Cancer Res. 2010 Aug 1;70(15):6377-83. doi: 10.1158/0008-5472.CAN-10-1180. Epub 2010 Jul 7.
• [6] A 15-gene signature for prediction of colon cancer recurrence and prognosis based on SVM.Gene. 2017 Mar 10;604:33-40. doi: 10.1016/j.gene.2016.12.016. Epub 2016 Dec 18.
• [7] PMEPA1, a transforming growth factor-beta-induced marker of terminal colonocyte differentiation whose expression is maintained in primary and metastatic colon cancer.Cancer Res. 2003 Apr 1;63(7):1568-75.
• [8] PMEPA1 induces EMT via a non-canonical TGF- signalling in colorectal cancer.J Cell Mol Med. 2019 May;23(5):3603-3615. doi: 10.1111/jcmm.14261. Epub 2019 Mar 19.
• [9] EGF- and cell-cycle-regulated STAG1/PMEPA1/ERG1.2 belongs to a conserved gene family and is overexpressed and amplified in breast and ovarian cancer.Mol Carcinog. 2003 Dec;38(4):188-200. doi: 10.1002/mc.10162.
• [10] Characterization of a novel gene, STAG1/PMEPA1, upregulated in renal cell carcinoma and other solid tumors.Mol Carcinog. 2001 Sep;32(1):44-53. doi: 10.1002/mc.1063.
• [11] TMEPAI regulates EMT in lung cancer cells by modulating the ROS and IRS-1 signaling pathways.Carcinogenesis. 2013 Aug;34(8):1764-72. doi: 10.1093/carcin/bgt132. Epub 2013 Apr 24.
• [12] TMEPAI inhibits TGF- signaling by promoting lysosome degradation of TGF- receptor and contributes to lung cancer development.Cell Signal. 2014 Sep;26(9):2030-9. doi: 10.1016/j.cellsig.2014.06.001. Epub 2014 Jun 13.
• [13] The TGF- Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone.Cancer Cell. 2015 Jun 8;27(6):809-21. doi: 10.1016/j.ccell.2015.04.009. Epub 2015 May 14.
• [14] Methylation of the PMEPA1 gene, a negative regulator of the androgen receptor in prostate cancer.Epigenetics. 2014 Jun;9(6):918-27. doi: 10.4161/epi.28710. Epub 2014 Apr 2.
• [15] NGS-based transcriptome profiling reveals biomarkers for companion diagnostics of the TGF- receptor blocker galunisertib in HCC.Cell Death Dis. 2017 Feb 23;8(2):e2634. doi: 10.1038/cddis.2017.44.
• [16] miR?9a?p targets PMEPA1 and induces prostate cancer cell proliferation, migration and invasion.Mol Med Rep. 2016 May;13(5):4030-8. doi: 10.3892/mmr.2016.5033. Epub 2016 Mar 21.
• [17] The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor.J Biol Chem. 2018 Apr 20;293(16):5847-5859. doi: 10.1074/jbc.RA117.000972. Epub 2018 Feb 21.
• [18] Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors.Cancer Res. 2005 Jan 1;65(1):166-76.
• [19] Development of Novel Monoclonal Antibodies for Evaluation of Transmembrane Prostate Androgen-Induced Protein 1 (TMEPAI) Expression Patterns in Gastric Cancer.Pathol Oncol Res. 2018 Apr;24(2):427-438. doi: 10.1007/s12253-017-0247-x. Epub 2017 Jun 5.
• [20] 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.
• [21] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] 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.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [26] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [27] 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.
• [28] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [29] 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.
• [30] A role for DNA methylation in regulating the growth suppressor PMEPA1 gene in prostate cancer. Epigenetics. 2007 Apr-Jun;2(2):100-9.
• [31] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [32] 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.
• [33] 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.
• [34] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [35] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [36] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [37] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [38] Characterisation of gene expression patterns in 22RV1 cells for determination of environmental androgenic/antiandrogenic compounds. J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):231-8. doi: 10.1016/s0960-0760(03)00033-5.
• [39] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [40] Androgen responsive and refractory prostate cancer cells exhibit distinct curcumin regulated transcriptome. Cancer Biol Ther. 2008 Sep;7(9):1427-35. doi: 10.4161/cbt.7.9.6469. Epub 2008 Sep 4.
• [41] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [42] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [43] 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.
• [44] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [45] 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.
• [46] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [47] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [48] 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.
• [49] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.