Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTETUPP5)

• DOT Name: Retinoic acid receptor responder protein 1 (RARRES1)
• Synonyms: Phorbol ester-induced gene 1 protein; PERG-1; RAR-responsive protein TIG1; Tazarotene-induced gene 1 protein
• Gene Name: RARRES1
• Related Disease:
  Glioblastoma multiforme
  Advanced cancer
  Benign prostatic hyperplasia
  Bladder cancer
  Breast cancer
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Endometrial carcinoma
  Endometriosis
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Fatty liver disease
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Hyperinsulinemia
  Inflammatory breast cancer
  leukaemia
  Leukemia
  Nasopharyngeal carcinoma
  Psoriasis
  Renal cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast carcinoma
  Carcinoma
  Choriocarcinoma
  Epstein barr virus infection
  Gastric cancer
  Fetal growth restriction
  Prostate cancer
  Prostate carcinoma
• UniProt ID: TIG1_HUMAN
• Pfam ID: PF20630 ; PF06907
• Sequence:
  MQPRRQRLPAPWSGPRGPRPTAPLLALLLLLAPVAAPAGSGDPDDPGQPQDAGVPRRLLQ
  QAARAALHFFNFRSGSPSALRVLAEVQEGRAWINPKEGCKVHVVFSTERYNPESLLQEGE
  GRLGKCSARVFFKNQKPRPTINVTCTRLIEKKKRQQEDYLLYKQMKQLKNPLEIVSIPDN
  HGHIDPSLRLIWDLAFLGSSYVMWEMTTQVSHYYLAQLTSVRQWKTNDDTIDFDYTVLLH
  ELSTQEIIPCRIHLVWYPGKPLKVKYHCQELQTPEEASGTEEGSAVVPTELSNF
• Function: Inhibitor of the cytoplasmic carboxypeptidase AGBL2, may regulate the alpha-tubulin tyrosination cycle.
• Tissue Specificity: Detected in urine (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[8]
Endometriosis	DISX1AG8	Strong	Altered Expression	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[10]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[11]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[12]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[14]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[13]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[12]
Inflammatory breast cancer	DIS3QRWA	Strong	Biomarker	[15]
leukaemia	DISS7D1V	Strong	Posttranslational Modification	[16]
Leukemia	DISNAKFL	Strong	Posttranslational Modification	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Posttranslational Modification	[17]
Psoriasis	DIS59VMN	Strong	Altered Expression	[18]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[10]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[19]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[5]
Carcinoma	DISH9F1N	moderate	Altered Expression	[19]
Choriocarcinoma	DISDBVNL	moderate	Biomarker	[20]
Epstein barr virus infection	DISOO0WT	moderate	Biomarker	[17]
Gastric cancer	DISXGOUK	moderate	Biomarker	[21]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[22]
Prostate cancer	DISF190Y	Limited	Altered Expression	[23]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[23]

18 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 Retinoic acid receptor responder protein 1 (RARRES1).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[26]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[27]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[28]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[29]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[30]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[31]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[28]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[32]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[25]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[25]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[36]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[25]
ORG2058	DMH1M6N	Investigative	ORG2058 increases the expression of Retinoic acid receptor responder protein 1 (RARRES1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Retinoic acid receptor responder protein 1 (RARRES1).	[34]

References

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• [2] Tumor suppressor RARRES1 links tubulin deglutamylation to mitochondrial metabolism and cell survival.Oncotarget. 2019 Feb 26;10(17):1606-1624. doi: 10.18632/oncotarget.26600. eCollection 2019 Feb 26.
• [3] Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing.Dis Markers. 2011;30(4):151-61. doi: 10.3233/DMA-2011-0790.
• [4] Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer.J Urol. 2008 Jan;179(1):346-52. doi: 10.1016/j.juro.2007.08.091. Epub 2007 Nov 19.
• [5] Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1.Oncotarget. 2016 Jul 12;7(28):44096-44112. doi: 10.18632/oncotarget.9858.
• [6] Expression and clinicopathological correlations of retinoid acid receptor responder protein 1 in renal cell carcinomas.Biomark Med. 2016 Jul;10(7):721-32. doi: 10.2217/bmm.16.12. Epub 2016 Jun 24.
• [7] G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells.BMC Cancer. 2011 May 17;11:175. doi: 10.1186/1471-2407-11-175.
• [8] Discovery of epigenetically masked tumor suppressor genes in endometrial cancer.Mol Cancer Res. 2005 May;3(5):261-9. doi: 10.1158/1541-7786.MCR-04-0110.
• [9] Genome-wide microarray gene expression, array-CGH analysis, and telomerase activity in advanced ovarian endometriosis: a high degree of differentiation rather than malignant potential.Int J Mol Med. 2008 Mar;21(3):335-44.
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• [11] Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma.Clin Cancer Res. 2004 Aug 15;10(16):5518-22. doi: 10.1158/1078-0432.CCR-04-0108.
• [12] Tumor suppressor RARRES1- A novel regulator of fatty acid metabolism in epithelial cells.PLoS One. 2018 Dec 17;13(12):e0208756. doi: 10.1371/journal.pone.0208756. eCollection 2018.
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• [17] Role of the RARRES1 gene in nasopharyngeal carcinoma.Cancer Genet Cytogenet. 2009 Oct;194(1):58-64. doi: 10.1016/j.cancergencyto.2009.06.005.
• [18] Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor-responsive gene in skin.J Invest Dermatol. 1996 Feb;106(2):269-74. doi: 10.1111/1523-1747.ep12340668.
• [19] Expression and mutation analysis of TIG1 (tazarotene-induced gene 1) in human gastric cancer.Oncol Res. 2009;17(11-12):571-80. doi: 10.3727/096504009789745584.
• [20] Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma.J Exp Clin Cancer Res. 2017 Nov 23;36(1):165. doi: 10.1186/s13046-017-0634-x.
• [21] Quantitative assessment of gene methylation in neoplastic and non-neoplastic gastric epithelia using methylation-specific DNA microarray.Pathol Int. 2009 Dec;59(12):895-9. doi: 10.1111/j.1440-1827.2009.02458.x.
• [22] Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta.Reprod Sci. 2018 Sep;25(9):1357-1370. doi: 10.1177/1933719117746761. Epub 2017 Dec 15.
• [23] Multiple roles of RARRES1 in prostate cancer: Autophagy induction and angiogenesis inhibition.PLoS One. 2017 Jul 5;12(7):e0180344. doi: 10.1371/journal.pone.0180344. eCollection 2017.
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• [26] 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.
• [27] DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line. Physiol Genomics. 2004 Apr 13;17(2):122-9. doi: 10.1152/physiolgenomics.00002.2003.
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• [33] 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.
• [34] 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.
• [35] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [36] 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.
• [37] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.