Details of Drug Off-Target (DOT)

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

• DOT Name: Forkhead box protein P4 (FOXP4)
• Synonyms: Fork head-related protein-like A
• Gene Name: FOXP4
• Related Disease:
  Advanced cancer
  Breast carcinoma
  Bone osteosarcoma
  Breast cancer
  Ewing sarcoma
  Kidney neoplasm
  Laryngeal carcinoma
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Osteoarthritis
  Osteosarcoma
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Hepatocellular carcinoma
  Asthma
  Prostate cancer
  Prostate neoplasm
  Squamous cell carcinoma
• UniProt ID: FOXP4_HUMAN
• PDB ID: 6XAT
• Pfam ID: PF00250 ; PF16159
• Sequence:
  MMVESASETIRSAPSGQNGVGSLSGQADGSSGGATGTTASGTGREVTTGADSNGEMSPAE
  LLHFQQQQALQVARQFLLQQASGLSSPGNNDSKQSASAVQVPVSVAMMSPQMLTPQQMQQ
  ILSPPQLQALLQQQQALMLQQLQEYYKKQQEQLHLQLLTQQQAGKPQPKEALGNKQLAFQ
  QQLLQMQQLQQQHLLNLQRQGLVSLQPNQASGPLQTLPQAAVCPTDLPQLWKGEGAPGQP
  AEDSVKQEGLDLTGTAATATSFAAPPKVSPPLSHHTLPNGQPTVLTSRRDSSSHEETPGS
  HPLYGHGECKWPGCETLCEDLGQFIKHLNTEHALDDRSTAQCRVQMQVVQQLEIQLAKES
  ERLQAMMAHLHMRPSEPKPFSQPLNPVPGSSSFSKVTVSAADSFPDGLVHPPTSAAAPVT
  PLRPPGLGSASLHGGGPARRRSSDKFCSPISSELAQNHEFYKNADVRPPFTYASLIRQAI
  LETPDRQLTLNEIYNWFTRMFAYFRRNTATWKNAVRHNLSLHKCFVRVENVKGAVWTVDE
  REYQKRRPPKMTGSPTLVKNMISGLSYGALNASYQAALAESSFPLLNSPGMLNPGSASSL
  LPLSHDDVGAPVEPLPSNGSSSPPRLSPPQYSHQVQVKEEPAEAEEDRQPGPPLGAPNPS
  ASGPPEDRDLEEELPGEELS
• Function: Transcriptional repressor that represses lung-specific expression.

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]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[3]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[4]
Laryngeal carcinoma	DISNHCIV	Strong	Altered Expression	[4]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Osteoarthritis	DIS05URM	Strong	Biomarker	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[9]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[6]
Asthma	DISW9QNS	Limited	Biomarker	[11]
Prostate cancer	DISF190Y	Limited	Altered Expression	[12]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Forkhead box protein P4 (FOXP4).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Forkhead box protein P4 (FOXP4).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein P4 (FOXP4).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Forkhead box protein P4 (FOXP4).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Forkhead box protein P4 (FOXP4).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Forkhead box protein P4 (FOXP4).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Forkhead box protein P4 (FOXP4).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Forkhead box protein P4 (FOXP4).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Forkhead box protein P4 (FOXP4).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Forkhead box protein P4 (FOXP4).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Forkhead box protein P4 (FOXP4).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Forkhead box protein P4 (FOXP4).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Forkhead box protein P4 (FOXP4).	[25]

References

• [1] Upregulation of FOXP4 in breast cancer promotes migration and invasion through facilitating EMT.Cancer Manag Res. 2019 Apr 8;11:2783-2793. doi: 10.2147/CMAR.S191641. eCollection 2019.
• [2] Up-regulation of microRNA-491-5p suppresses cell proliferation and promotes apoptosis by targeting FOXP4 in human osteosarcoma.Cell Prolif. 2017 Feb;50(1):e12308. doi: 10.1111/cpr.12308. Epub 2016 Oct 5.
• [3] LncRNA SOX2 overlapping transcript acts as a miRNA sponge to promote the proliferation and invasion of Ewing's sarcoma.Am J Transl Res. 2019 Jun 15;11(6):3841-3849. eCollection 2019.
• [4] FoxP4, a novel forkhead transcription factor.Biochim Biophys Acta. 2003 Jun 19;1627(2-3):147-52. doi: 10.1016/s0167-4781(03)00074-5.
• [5] Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma.Nat Commun. 2016 Aug 9;7:12451. doi: 10.1038/ncomms12451.
• [6] Upregulation of FoxP4 in HCC promotes migration and invasion through regulation of EMT.Oncol Lett. 2019 Apr;17(4):3944-3951. doi: 10.3892/ol.2019.10049. Epub 2019 Feb 19.
• [7] FOXP4 modulates tumor growth and independently associates with miR-138 in non-small cell lung cancer cells.Tumour Biol. 2015 Sep;36(10):8185-91. doi: 10.1007/s13277-015-3498-8. Epub 2015 May 21.
• [8] Identification of differentially methylated regions in new genes associated with knee osteoarthritis.Gene. 2016 Jan 15;576(1 Pt 2):312-8. doi: 10.1016/j.gene.2015.10.037. Epub 2015 Oct 17.
• [9] 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population.Nat Commun. 2019 Sep 27;10(1):4422. doi: 10.1038/s41467-019-12267-6.
• [10] CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR-138-5p in renal carcinoma.J Cell Physiol. 2019 Jul;234(7):10646-10654. doi: 10.1002/jcp.27744. Epub 2018 Nov 27.
• [11] Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness.J Clin Invest. 2016 May 2;126(5):1978-82. doi: 10.1172/JCI81389. Epub 2016 Apr 18.
• [12] LncRNA FOXP4-AS1 is activated by PAX5 and promotes the growth of prostate cancer by sequestering miR-3184-5p to upregulate FOXP4.Cell Death Dis. 2019 Jun 17;10(7):472. doi: 10.1038/s41419-019-1699-6.
• [13] Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population.Nat Genet. 2010 Sep;42(9):751-4. doi: 10.1038/ng.635. Epub 2010 Aug 1.
• [14] MicroRNA-299-3p/FOXP4 Axis Regulates the Proliferation and Migration of Oral Squamous Cell Carcinoma.Technol Cancer Res Treat. 2019 Jan 1;18:1533033819874803. doi: 10.1177/1533033819874803.
• [15] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] 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.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.