Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNVO2B6)

• DOT Name: Nuclear receptor subfamily 2 group F member 6 (NR2F6)
• Synonyms: V-erbA-related protein 2; EAR-2
• Gene Name: NR2F6
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Alzheimer disease
  Autoimmune disease
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Colitis
  Endometriosis
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Acute myelogenous leukaemia
  Breast cancer
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
• UniProt ID: NR2F6_HUMAN
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MAMVTGGWGGPGGDTNGVDKAGGYPRAAEDDSASPPGAASDAEPGDEERPGLQVDCVVCG
  DKSSGKHYGVFTCEGCKSFFKRSIRRNLSYTCRSNRDCQIDQHHRNQCQYCRLKKCFRVG
  MRKEAVQRGRIPHSLPGAVAASSGSPPGSALAAVASGGDLFPGQPVSELIAQLLRAEPYP
  AAAGRFGAGGGAAGAVLGIDNVCELAARLLFSTVEWARHAPFFPELPVADQVALLRLSWS
  ELFVLNAAQAALPLHTAPLLAAAGLHAAPMAAERAVAFMDQVRAFQEQVDKLGRLQVDSA
  EYGCLKAIALFTPDACGLSDPAHVESLQEKAQVALTEYVRAQYPSQPQRFGRLLLRLPAL
  RAVPASLISQLFFMRLVGKTPIETLIRDMLLSGSTFNWPYGSGQ
• Function: Transcription factor predominantly involved in transcriptional repression. Binds to promoter/enhancer response elements that contain the imperfect 5'-AGGTCA-3' direct or inverted repeats with various spacings which are also recognized by other nuclear hormone receptors. Involved in modulation of hormonal responses. Represses transcriptional activity of the lutropin-choriogonadotropic hormone receptor/LHCGR gene, the renin/REN gene and the oxytocin-neurophysin/OXT gene. Represses the triiodothyronine-dependent and -independent transcriptional activity of the thyroid hormone receptor gene in a cell type-specific manner. The corepressing function towards thyroid hormone receptor beta/THRB involves at least in part the inhibition of THRB binding to triiodothyronine response elements (TREs) by NR2F6. Inhibits NFATC transcription factor DNA binding and subsequently its transcriptional activity. Acts as transcriptional repressor of IL-17 expression in Th-17 differentiated CD4(+) T cells and may be involved in induction and/or maintenance of peripheral immunological tolerance and autoimmunity. Involved in development of forebrain circadian clock; is required early in the development of the locus coeruleus (LC).
• Tissue Specificity: Expressed in heart, placenta, liver, skeletal muscle, kidney and pancreas.
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Altered Expression	[6]
Endometriosis	DISX1AG8	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[5]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[12]
Colon cancer	DISVC52G	Limited	Biomarker	[13]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[13]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[21]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[25]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Nuclear receptor subfamily 2 group F member 6 (NR2F6).	[24]

References

• [1] Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression.Mol Cancer. 2019 Jul 19;18(1):119. doi: 10.1186/s12943-019-1046-7.
• [2] Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway.Int J Cancer. 2019 Oct 1;145(7):1921-1934. doi: 10.1002/ijc.32293. Epub 2019 Apr 4.
• [3] Magnetic resonance imaging of noradrenergic neurons.Brain Struct Funct. 2019 May;224(4):1609-1625. doi: 10.1007/s00429-019-01858-0. Epub 2019 Mar 22.
• [4] Orphan nuclear receptor NR2F6 acts as an essential gatekeeper of Th17 CD4+ T cell effector functions.Cell Commun Signal. 2014 Jun 12;12:38. doi: 10.1186/1478-811X-12-38.
• [5] NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer.Int J Mol Sci. 2016 Oct 20;17(10):1694. doi: 10.3390/ijms17101694.
• [6] Nuclear orphan receptor NR2F6 as a safeguard against experimental murine colitis.Gut. 2018 Aug;67(8):1434-1444. doi: 10.1136/gutjnl-2016-313466. Epub 2017 Aug 4.
• [7] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [8] MiR-142-3p suppresses the proliferation, migration and invasion through inhibition of NR2F6 in lung adenocarcinoma.Hum Cell. 2019 Oct;32(4):437-446. doi: 10.1007/s13577-019-00258-0. Epub 2019 Jun 5.
• [9] Cutaneous Squamous Cell Carcinoma With Sclerosing Features: An Uncommon and Potentially Aggressive Variant.Am J Dermatopathol. 2018 Aug;40(8):575-579. doi: 10.1097/DAD.0000000000001169.
• [10] Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade.Nat Commun. 2018 Apr 18;9(1):1538. doi: 10.1038/s41467-018-04004-2.
• [11] DDA1 is induced by NR2F6 in ovarian cancer and predicts poor survival outcome.Eur Rev Med Pharmacol Sci. 2017 Mar;21(6):1206-1213.
• [12] Modulation of aromatase expression in human breast tissue. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):35-40.
• [13] The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells.Cancer Lett. 2011 Oct 28;309(2):137-44. doi: 10.1016/j.canlet.2011.05.025. Epub 2011 Jun 22.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [18] 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.
• [19] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [20] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [21] 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.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.