Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1KQIUX)

• DOT Name: Transcription factor AP-4 (TFAP4)
• Synonyms: Activating enhancer-binding protein 4; Class C basic helix-loop-helix protein 41; bHLHc41
• Gene Name: TFAP4
• Related Disease:
  Advanced cancer
  Burkitt lymphoma
  Cerebral palsy
  Hepatocellular carcinoma
  Gastric cancer
  Stomach cancer
  Neoplasm
  Colorectal carcinoma
  Neuroblastoma
• UniProt ID: TFAP4_HUMAN
• Pfam ID: PF00010
• Sequence:
  MEYFMVPTQKVPSLQHFRKTEKEVIGGLCSLANIPLTPETQRDQERRIRREIANSNERRR
  MQSINAGFQSLKTLIPHTDGEKLSKAAILQQTAEYIFSLEQEKTRLLQQNTQLKRFIQEL
  SGSSPKRRRAEDKDEGIGSPDIWEDEKAEDLRREMIELRQQLDKERSVRMMLEEQVRSLE
  AHMYPEKLKVIAQQVQLQQQQEQVRLLHQEKLEREQQQLRTQLLPPPAPTHHPTVIVPAP
  PPPPSHHINVVTMGPSSVINSVSTSRQNLDTIVQAIQHIEGTQEKQELEEEQRRAVIVKP
  VRSCPEAPTSDTASDSEASDSDAMDQSREEPSGDGELP
• Function: Transcription factor that activates both viral and cellular genes by binding to the symmetrical DNA sequence 5'-CAGCTG-3'.
• KEGG Pathway: Proteoglycans in cancer (hsa05205)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[2]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[5]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[5]
Neoplasm	DISZKGEW	Disputed	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[7]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription factor AP-4 (TFAP4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor AP-4 (TFAP4).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription factor AP-4 (TFAP4).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcription factor AP-4 (TFAP4).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcription factor AP-4 (TFAP4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor AP-4 (TFAP4).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor AP-4 (TFAP4).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor AP-4 (TFAP4).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor AP-4 (TFAP4).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transcription factor AP-4 (TFAP4).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transcription factor AP-4 (TFAP4).	[14]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Transcription factor AP-4 (TFAP4).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor AP-4 (TFAP4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor AP-4 (TFAP4).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription factor AP-4 (TFAP4).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcription factor AP-4 (TFAP4).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Transcription factor AP-4 (TFAP4).	[23]

References

• [1] The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression.Nat Commun. 2017 Feb 14;8:14418. doi: 10.1038/ncomms14418.
• [2] Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma.BMC Cancer. 2017 Nov 13;17(1):761. doi: 10.1186/s12885-017-3711-9.
• [3] Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population.Mol Biol Rep. 2013 Nov;40(11):6459-67. doi: 10.1007/s11033-013-2761-6. Epub 2013 Sep 25.
• [4] Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/-catenin pathway in hepatocellular carcinoma.Theranostics. 2018 Jun 7;8(13):3571-3583. doi: 10.7150/thno.25194. eCollection 2018.
• [5] miR-144 suppresses cell proliferation and invasion in gastric cancer through downregulation of activating enhancer-binding protein 4.Oncol Lett. 2019 Jun;17(6):5686-5692. doi: 10.3892/ol.2019.10214. Epub 2019 Apr 4.
• [6] Evaluating the prognostic value and functional roles of transcription factor AP4 in colorectal cancer.Oncol Lett. 2018 May;15(5):7545-7554. doi: 10.3892/ol.2018.8290. Epub 2018 Mar 16.
• [7] MicroRNA-302c represses epithelial-mesenchymal transition and metastasis by targeting transcription factor AP-4 in colorectal cancer.Biomed Pharmacother. 2018 Sep;105:670-676. doi: 10.1016/j.biopha.2018.06.025. Epub 2018 Jun 12.
• [8] Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma.Oncogene. 2018 Oct;37(40):5451-5465. doi: 10.1038/s41388-018-0326-9. Epub 2018 Jun 7.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] 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.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.