Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ANHVT)

• DOT Name: Protein BTG3 (BTG3)
• Synonyms: Abundant in neuroepithelium area protein; BTG family member 3; Protein Tob5
• Gene Name: BTG3
• Related Disease:
  Lung adenocarcinoma
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Epithelial ovarian cancer
  Gastric cancer
  Hepatitis C virus infection
  High blood pressure
  Lung carcinoma
  Lupus
  Medulloblastoma
  Neoplasm
  Oral cancer
  Ovarian cancer
  Papillary renal cell carcinoma
  Primary biliary cholangitis
  Renal cell carcinoma
  Rheumatoid arthritis
  Sjogren syndrome
  Stomach cancer
  Thrombocytopenia
  Vasculitis
  Autoimmune disease
  Hepatocellular carcinoma
  Lung cancer
  Anxiety
  Anxiety disorder
  Arthritis
  Bone osteosarcoma
  Cholestasis
  Colorectal carcinoma
  Juvenile idiopathic arthritis
  Non-small-cell lung cancer
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Scleroderma
  Systemic lupus erythematosus
  Type-1/2 diabetes
• UniProt ID: BTG3_HUMAN
• Pfam ID: PF07742
• Sequence:
  MKNEIAAVVFFFTRLVRKHDKLKKEAVERFAEKLTLILQEKYKNHWYPEKPSKGQAYRCI
  RVNKFQRVDPDVLKACENSCILYSDLGLPKELTLWVDPCEVCCRYGEKNNAFIVASFENK
  DENKDEISRKVTRALDKVTSDYHSGSSSSDEETSKEMEVKPSSVTAAASPVYQISELIFP
  PLPMWHPLPRKKPGMYRGNGHQNHYPPPVPFGYPNQGRKNKPYRPIPVTWVPPPGMHCDR
  NHWINPHMLAPH
• Function: Overexpression impairs serum-induced cell cycle progression from the G0/G1 to S phase.
• Tissue Specificity: Ubiquitous. High expression in the ventricular zone of the developing central nervous system. High in ovary, testis, prostate, thymus and lung.
• KEGG Pathway: R. degradation (hsa03018)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[3]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
High blood pressure	DISY2OHH	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Lupus	DISOKJWA	Strong	Biomarker	[10]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Oral cancer	DISLD42D	Strong	Biomarker	[13]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[14]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[4]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[15]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[15]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[16]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[15]
Vasculitis	DISQRKDX	Strong	Biomarker	[17]
Autoimmune disease	DISORMTM	moderate	Biomarker	[18]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[19]
Lung cancer	DISCM4YA	moderate	Altered Expression	[14]
Anxiety	DISIJDBA	Limited	Biomarker	[20]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[20]
Arthritis	DIST1YEL	Limited	Genetic Variation	[21]
Bone osteosarcoma	DIST1004	Limited	Genetic Variation	[22]
Cholestasis	DISDJJWE	Limited	Biomarker	[23]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[24]
Juvenile idiopathic arthritis	DISQZGBV	Limited	Biomarker	[25]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[26]
Osteosarcoma	DISLQ7E2	Limited	Genetic Variation	[22]
Prostate cancer	DISF190Y	Limited	Altered Expression	[27]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[27]
Scleroderma	DISVQ342	Limited	Biomarker	[28]
Systemic lupus erythematosus	DISI1SZ7	Limited	Biomarker	[29]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein BTG3 (BTG3).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein BTG3 (BTG3).	[41]

20 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 Protein BTG3 (BTG3).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein BTG3 (BTG3).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein BTG3 (BTG3).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein BTG3 (BTG3).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein BTG3 (BTG3).	[36]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein BTG3 (BTG3).	[32]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Protein BTG3 (BTG3).	[4]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Protein BTG3 (BTG3).	[38]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Protein BTG3 (BTG3).	[39]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Protein BTG3 (BTG3).	[38]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Protein BTG3 (BTG3).	[38]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Protein BTG3 (BTG3).	[38]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Protein BTG3 (BTG3).	[38]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Protein BTG3 (BTG3).	[40]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein BTG3 (BTG3).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein BTG3 (BTG3).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein BTG3 (BTG3).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein BTG3 (BTG3).	[44]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein BTG3 (BTG3).	[45]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Protein BTG3 (BTG3).	[46]

References

• [1] Regulation of transforming growth factor beta1 by nitric oxide.Cancer Res. 1999 May 1;59(9):2142-9.
• [2] Autoantibody status in systemic sclerosis patients defines both cancer risk and survival with ANA negativity in cases with concomitant cancer having a worse survival.Oncoimmunology. 2019 Mar 24;8(6):e1588084. doi: 10.1080/2162402X.2019.1588084. eCollection 2019.
• [3] Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer.Oncogene. 2018 Sep;37(39):5257-5268. doi: 10.1038/s41388-018-0347-4. Epub 2018 May 31.
• [4] BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis. 2009 Apr;30(4):662-70. doi: 10.1093/carcin/bgp042. Epub 2009 Feb 12.
• [5] BTG3 Overexpression Suppresses the Proliferation and Invasion in Epithelial Ovarian Cancer Cell by Regulating AKT/GSK3/-Catenin Signaling.Reprod Sci. 2017 Oct;24(10):1462-1468. doi: 10.1177/1933719117691143. Epub 2017 Feb 9.
• [6] The roles of BTG3 expression in gastric cancer: a potential marker for carcinogenesis and a target molecule for gene therapy.Oncotarget. 2015 Aug 14;6(23):19841-67. doi: 10.18632/oncotarget.3734.
• [7] High prevalence of a variety of autoantibodies in a population of hepatitis C virus-infected individuals.APMIS. 2018 Jun;126(6):515-522. doi: 10.1111/apm.12850.
• [8] MiRNA and mRNA Profiling in Systemic Lupus Reveals a Novel Set of Cytokine - Related miRNAs and their Target Genes in Cases With and Without Renal Involvement.Kidney Blood Press Res. 2017;42(6):1322-1337. doi: 10.1159/000485987. Epub 2017 Dec 15.
• [9] Downregulation of BTG3 in non-small cell lung cancer.Biochem Biophys Res Commun. 2013 Jul 19;437(1):173-8. doi: 10.1016/j.bbrc.2013.06.062. Epub 2013 Jun 26.
• [10] Rare diseases that mimic Systemic Lupus Erythematosus (Lupus mimickers).Joint Bone Spine. 2019 Mar;86(2):165-171. doi: 10.1016/j.jbspin.2018.10.007. Epub 2018 Oct 26.
• [11] Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma.Front Pharmacol. 2019 Jun 26;10:698. doi: 10.3389/fphar.2019.00698. eCollection 2019.
• [12] Oleuropein inhibits esophageal cancer through hypoxic suppression of BTG3 mRNA.Food Funct. 2019 Feb 20;10(2):978-985. doi: 10.1039/c8fo02223b.
• [13] Modulation of BDNF-TRKB Interactions on Schwann Cell-induced Oral Squamous Cell Carcinoma Dispersion In Vitro.Anticancer Res. 2019 Nov;39(11):5933-5942. doi: 10.21873/anticanres.13798.
• [14] ASBEL, an ANA/BTG3 antisense transcript required for tumorigenicity of ovarian carcinoma.Sci Rep. 2013;3:1305. doi: 10.1038/srep01305.
• [15] Prevalence of autoimmune diseases and clinical significance of autoantibody profile: Data from National Institute of Hygiene in Rabat, Morocco.Hum Immunol. 2019 Jul;80(7):523-532. doi: 10.1016/j.humimm.2019.02.012. Epub 2019 Feb 23.
• [16] Primary Sjgren's syndrome.Lupus. 2018 Oct;27(1_suppl):32-35. doi: 10.1177/0961203318801673.
• [17] Adult-onset Alexander disease with a heterozygous D128N GFAP mutation: a pathological study.Histol Histopathol. 2019 Sep;34(9):1073-188. doi: 10.14670/HH-18-110. Epub 2019 Apr 3.
• [18] Validation of the 2019 European League Against Rheumatism/American College of Rheumatology Criteria Compared to the 1997 American College of Rheumatology Criteria and the 2012 Systemic Lupus International Collaborating Clinics Criteria in Pediatric Systemic Lupus Erythematosus.Arthritis Care Res (Hoboken). 2020 Nov;72(11):1597-1601. doi: 10.1002/acr.24057.
• [19] MicroRNA-519c-3p promotes tumor growth and metastasis of hepatocellular carcinoma by targeting BTG3.Biomed Pharmacother. 2019 Oct;118:109267. doi: 10.1016/j.biopha.2019.109267. Epub 2019 Aug 3.
• [20] Blockade of TrkB receptors in the nucleus accumbens prior to heterotypic stress alters corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway.Horm Behav. 2017 Apr;90:98-112. doi: 10.1016/j.yhbeh.2017.02.012. Epub 2017 Mar 15.
• [21] Estrogen receptor alpha gene ( ESR1) polymorphism can contribute to clinical findings in systemic lupus erythematosus patients.Lupus. 2017 Mar;26(3):294-298. doi: 10.1177/0961203316668041. Epub 2016 Sep 29.
• [22] Long non-coding RNA ASBEL promotes osteosarcoma cell proliferation, migration, and invasion by regulating microRNA-21.J Cell Biochem. 2018 Aug;119(8):6461-6469. doi: 10.1002/jcb.26671. Epub 2018 May 9.
• [23] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [24] Cucurbitacin B inhibits cell proliferation and induces cell apoptosis in colorectal cancer by modulating methylation status of BTG3.Neoplasma. 2019 Jul 23;66(4):593-602. doi: 10.4149/neo_2018_180929N729. Epub 2019 Apr 24.
• [25] Risk Factors and Biomarkers for the Occurrence of Uveitis in Juvenile Idiopathic Arthritis: Data From the Inception Cohort of Newly Diagnosed Patients With Juvenile Idiopathic Arthritis Study.Arthritis Rheumatol. 2018 Oct;70(10):1685-1694. doi: 10.1002/art.40544. Epub 2018 Aug 21.
• [26] Regulation of BTG3 by microRNA-20b-5p in non-small cell lung cancer.Oncol Lett. 2019 Jul;18(1):137-144. doi: 10.3892/ol.2019.10333. Epub 2019 May 7.
• [27] Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis.Oncogene. 2012 Jul 5;31(27):3287-97. doi: 10.1038/onc.2011.491. Epub 2011 Oct 24.
• [28] Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis.Rheumatology (Oxford). 2018 Apr 1;57(4):712-717. doi: 10.1093/rheumatology/kex458.
• [29] Increased Incidence of Resistant Hypertension in Patients With Systemic Lupus Erythematosus: A Retrospective Cohort Study.Arthritis Care Res (Hoboken). 2020 Apr;72(4):534-543. doi: 10.1002/acr.23880.
• [30] Real world clinical outcomes and patient characteristics for canagliflozin treated patients in a specialty diabetes clinic.Curr Med Res Opin. 2017 Jan;33(1):77-84. doi: 10.1080/03007995.2016.1238354. Epub 2016 Oct 5.
• [31] 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.
• [32] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [33] 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.
• [34] 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.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [37] BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis. 2009 Apr;30(4):662-70. doi: 10.1093/carcin/bgp042. Epub 2009 Feb 12.
• [38] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [39] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [40] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [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] 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.
• [43] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [44] 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.
• [45] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [46] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.