Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9UB5UO)

• DOT Name: Homologous-pairing protein 2 homolog (PSMC3IP)
• Synonyms: Nuclear receptor coactivator GT198; PSMC3-interacting protein; Proteasome 26S ATPase subunit 3-interacting protein; Tat-binding protein 1-interacting protein; TBP-1-interacting protein
• Gene Name: PSMC3IP
• Related Disease:
  Advanced cancer
  Azoospermia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Hepatocellular carcinoma
  Neoplasm
  Ovarian dysgenesis 1
  Ovarian dysgenesis 3
  Perrault syndrome
  Prostate cancer
  Prostate neoplasm
  Triple negative breast cancer
  Female hypogonadism
  46 XX gonadal dysgenesis
  Carcinoma
  Epithelial ovarian cancer
  Fallopian tube carcinoma
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: HOP2_HUMAN
• Pfam ID: PF18517 ; PF07106
• Sequence:
  MSKGRAEAAAGAAGILLRYLQEQNRPYSSQDVFGNLQREHGLGKAVVVKTLEQLAQQGKI
  KEKMYGKQKIYFADQDQFDMVSDADLQVLDGKIVALTAKVQSLQQSCRYMEAELKELSSA
  LTTPEMQKEIQELKKECAGYRERLKNIKAATNHVTPEEKEQVYRERQKYCKEWRKRKRMA
  TELSDAILEGYPKSKKQFFEEVGIETDEDYNVTLPDP
• Function: Plays an important role in meiotic recombination. Stimulates DMC1-mediated strand exchange required for pairing homologous chromosomes during meiosis. The complex PSMC3IP/MND1 binds DNA, stimulates the recombinase activity of DMC1 as well as DMC1 D-loop formation from double-strand DNA. This complex stabilizes presynaptic RAD51 and DMC1 filaments formed on single strand DNA to capture double-strand DNA. This complex stimulates both synaptic and presynaptic critical steps in RAD51 and DMC1-promoted homologous pairing. May inhibit HIV-1 viral protein TAT activity and modulate the activity of proteasomes through association with PSMC3. Acts as a tissue specific coactivator of hormone-dependent transcription mediated by nuclear receptors.
• Tissue Specificity: Highly expressed in testis and colon.
• Reactome Pathway: Meiotic recombination (R-HSA-912446)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Azoospermia	DIS94181	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Ovarian dysgenesis 1	DISXIXHW	Strong	Genetic Variation	[2]
Ovarian dysgenesis 3	DISGRYE2	Strong	Autosomal recessive	[5]
Perrault syndrome	DISG2YOV	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[8]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[2]
46 XX gonadal dysgenesis	DISBB9HA	Supportive	Autosomal dominant	[9]
Carcinoma	DISH9F1N	Limited	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[10]
Fallopian tube carcinoma	DIST7A80	Limited	Genetic Variation	[10]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[19]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[20]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[21]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[22]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[23]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[15]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[15]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[30]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Homologous-pairing protein 2 homolog (PSMC3IP).	[31]

References

• [1] Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis.Oncotarget. 2017 May 25;8(31):51591-51607. doi: 10.18632/oncotarget.18196. eCollection 2017 Aug 1.
• [2] Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation.J Clin Endocrinol Metab. 2018 Feb 1;103(2):555-563. doi: 10.1210/jc.2017-01966.
• [3] Knockdown of PSMC3IP suppresses the proliferation and xenografted tumorigenesis of hepatocellular carcinoma cell.J Cell Biochem. 2019 Apr;120(4):5449-5458. doi: 10.1002/jcb.27824. Epub 2018 Oct 25.
• [4] GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer.Am J Pathol. 2016 May;186(5):1340-50. doi: 10.1016/j.ajpath.2016.01.006. Epub 2016 Mar 18.
• [5] The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis. Dev Cell. 2003 Dec;5(6):927-36. doi: 10.1016/s1534-5807(03)00369-1.
• [6] Genotype and phenotype heterogeneity in perrault syndrome.J Pediatr Adolesc Gynecol. 2013 Feb;26(1):e25-7. doi: 10.1016/j.jpag.2012.10.008.
• [7] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [8] Breast cancer genes PSMC3IP and EPSTI1 play a role in apoptosis regulation.PLoS One. 2015 Jan 15;10(1):e0115352. doi: 10.1371/journal.pone.0115352. eCollection 2015.
• [9] XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am J Hum Genet. 2011 Oct 7;89(4):572-9. doi: 10.1016/j.ajhg.2011.09.006. Epub 2011 Sep 29.
• [10] Human ovarian cancer stroma contains luteinized theca cells harboring tumor suppressor gene GT198 mutations.J Biol Chem. 2013 Nov 15;288(46):33387-97. doi: 10.1074/jbc.M113.485581. Epub 2013 Oct 4.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [19] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [20] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [21] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [22] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [23] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [24] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [25] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [26] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [27] 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.
• [28] 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.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] Identification of palmitate-regulated genes in HepG2 cells by applying microarray analysis. Biochim Biophys Acta. 2007 Sep;1770(9):1283-8. doi: 10.1016/j.bbagen.2007.07.001. Epub 2007 Jul 10.