Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFZOOQ9)

• DOT Name: Nuclear receptor subfamily 6 group A member 1 (NR6A1)
• Synonyms: Germ cell nuclear factor; GCNF; hGCNF; Retinoid receptor-related testis-specific receptor; RTR; hRTR
• Gene Name: NR6A1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Seminoma
  Choriocarcinoma
  Castration-resistant prostate carcinoma
  Pneumocystis pneumonia
• UniProt ID: NR6A1_HUMAN
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MERDEPPPSGGGGGGGSAGFLEPPAALPPPPRNGFCQDELAELDPGTISVSDDRAEQRTC
  LICGDRATGLHYGIISCEGCKGFFKRSICNKRVYRCSRDKNCVMSRKQRNRCQYCRLLKC
  LQMGMNRKAIREDGMPGGRNKSIGPVQISEEEIERIMSGQEFEEEANHWSNHGDSDHSSP
  GNRASESNQPSPGSTLSSSRSVELNGFMAFREQYMGMSVPPHYQYIPHLFSYSGHSPLLP
  QQARSLDPQSYSLIHQLLSAEDLEPLGTPMLIEDGYAVTQAELFALLCRLADELLFRQIA
  WIKKLPFFCELSIKDYTCLLSSTWQELILLSSLTVYSKQIFGELADVTAKYSPSDEELHR
  FSDEGMEVIERLIYLYHKFHQLKVSNEEYACMKAINFLNQDIRGLTSASQLEQLNKRYWY
  ICQDFTEYKYTHQPNRFPDLMMCLPEIRYIAGKMVNVPLEQLPLLFKVVLHSCKTSVGKE
• Function: Orphan nuclear receptor. Binds to a response element containing the sequence 5'-TCAAGGTCA-3'. May be involved in the regulation of gene expression in germ cell development during gametogenesis.
• Tissue Specificity: Shows highest expression in the germ cells of the adult testis.
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Seminoma	DIS3J8LJ	Strong	Genetic Variation	[3]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[4]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[5]
Pneumocystis pneumonia	DISFSOM3	Limited	Genetic Variation	[6]

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 Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[16]

11 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 Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the activity of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[12]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[17]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Nuclear receptor subfamily 6 group A member 1 (NR6A1).	[18]

References

• [1] NR6A1 couples with cAMP response element binding protein and regulates vascular smooth muscle cell migration.Int J Biochem Cell Biol. 2015 Dec;69:225-32. doi: 10.1016/j.biocel.2015.10.026. Epub 2015 Nov 4.
• [2] Positive expression of NR6A1/CT150 as a predictor of biochemical recurrence-free survival in prostate cancer patients.Oncotarget. 2016 Aug 31;8(38):64427-64439. doi: 10.18632/oncotarget.11749. eCollection 2017 Sep 8.
• [3] Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures.Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17763-8. doi: 10.1073/pnas.0509082102. Epub 2005 Nov 23.
• [4] Characterization of the expression of the retinoid-related, testis-associated receptor (RTR) in trophoblasts.Placenta. 2002 Apr;23(4):281-7. doi: 10.1053/plac.2001.0779.
• [5] Expression screening of cancer/testis genes in prostate cancer identifies NR6A1 as a novel marker of disease progression and aggressiveness.Prostate. 2013 Jul;73(10):1103-14. doi: 10.1002/pros.22659. Epub 2013 Mar 26.
• [6] Outbreak of pneumocystis pneumonia in renal and liver transplant patients caused by genotypically distinct strains of Pneumocystis jirovecii.Transplantation. 2013 Nov 15;96(9):834-42. doi: 10.1097/TP.0b013e3182a1618c.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3. J Biol Chem. 2006 Nov 3;281(44):33497-504. doi: 10.1074/jbc.M606975200. Epub 2006 Sep 5.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [13] Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact. 2009 May 15;179(2-3):288-96.
• [14] Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS One. 2011 Jan 18;6(1):e15766.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.