Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0DO6ZU)

• DOT Name: Homeobox protein Nkx-3.1 (NKX3-1)
• Synonyms: Homeobox protein NK-3 homolog A
• Gene Name: NKX3-1
• UniProt ID: NKX31_HUMAN
• PDB ID: 2L9R
• Pfam ID: PF00046
• Sequence:
  MLRVPEPRPGEAKAEGAAPPTPSKPLTSFLIQDILRDGAQRQGGRTSSQRQRDPEPEPEP
  EPEGGRSRAGAQNDQLSTGPRAAPEEAETLAETEPERHLGSYLLDSENTSGALPRLPQTP
  KQPQKRSRAAFSHTQVIELERKFSHQKYLSAPERAHLAKNLKLTETQVKIWFQNRRYKTK
  RKQLSSELGDLEKHSSLPALKEEAFSRASLVSVYNSYPYYPYLYCVGSWSPAFW
• Function: Transcription factor, which binds preferentially the consensus sequence 5'-TAAGT[AG]-3' and can behave as a transcriptional repressor. Plays an important role in normal prostate development, regulating proliferation of glandular epithelium and in the formation of ducts in prostate. Acts as a tumor suppressor controlling prostate carcinogenesis, as shown by the ability to inhibit proliferation and invasion activities of PC-3 prostate cancer cells.
• Tissue Specificity: Highly expressed in the prostate and, at a lower level, in the testis.
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Prostate cancer (hsa05215)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[12]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[13]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[14]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[15]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[16]
Flutamide	DMK0O7U	Approved	Flutamide decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[19]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[21]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[22]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[24]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[26]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[19]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[27]
[3H]mibolerone	DM6HDKQ	Investigative	[3H]mibolerone increases the expression of Homeobox protein Nkx-3.1 (NKX3-1).	[28]

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 affects the methylation of Homeobox protein Nkx-3.1 (NKX3-1).	[23]

References

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• [6] 17beta-Estradiol differentially regulates androgen-responsive genes through estrogen receptor-beta- and extracellular-signal regulated kinase-dependent pathways in LNCaP human prostate cancer cells. Mol Carcinog. 2007 Feb;46(2):117-29. doi: 10.1002/mc.20254.
• [7] Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis. 2001 Mar;22(3):409-14. doi: 10.1093/carcin/22.3.409.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] A role for DNA methylation in regulating the growth suppressor PMEPA1 gene in prostate cancer. Epigenetics. 2007 Apr-Jun;2(2):100-9.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer. Mol Cancer Ther. 2017 Aug;16(8):1521-1530. doi: 10.1158/1535-7163.MCT-16-0912. Epub 2017 May 12.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [14] Effects of 9-cis retinoic acid on human homeobox gene NKX3.1 expression in prostate cancer cell line LNCaP. Asian J Androl. 2006 Jul;8(4):435-41. doi: 10.1111/j.1745-7262.2006.00171.x.
• [15] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] Curcumin downregulates homeobox gene NKX3.1 in prostate cancer cell LNCaP. Acta Pharmacol Sin. 2007 Mar;28(3):423-30. doi: 10.1111/j.1745-7254.2007.00501.x.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Characterisation of gene expression patterns in 22RV1 cells for determination of environmental androgenic/antiandrogenic compounds. J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):231-8. doi: 10.1016/s0960-0760(03)00033-5.
• [20] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [21] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [22] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [23] 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.
• [24] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [25] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [26] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [27] Molecular signatures of soy-derived phytochemicals in androgen-responsive prostate cancer cells: a comparison study using DNA microarray. Mol Carcinog. 2006 Dec;45(12):943-56.
• [28] A nonsteroidal anti-inflammatory drug, flufenamic acid, inhibits the expression of the androgen receptor in LNCaP cells. Endocrinology. 1999 Nov;140(11):5451-4. doi: 10.1210/endo.140.11.7246.