Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6SW5H0)

• DOT Name: POU domain, class 4, transcription factor 2 (POU4F2)
• Synonyms: Brain-specific homeobox/POU domain protein 3B; Brain-3B; Brn-3B
• Gene Name: POU4F2
• Related Disease:
  Breast cancer
  Neoplasm
  Advanced cancer
  Bladder cancer
  Lung squamous cell carcinoma
  Neuroblastoma
  Systemic lupus erythematosus
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast carcinoma
  Breast neoplasm
  Lung cancer
  Small-cell lung cancer
• UniProt ID: PO4F2_HUMAN
• Pfam ID: PF00046 ; PF00157
• Sequence:
  MMMMSLNSKQAFSMPHGGSLHVEPKYSALHSTSPGSSAPIAPSASSPSSSSNAGGGGGGG
  GGGGGGGGRSSSSSSSGSSGGGGSEAMRRACLPTPPSNIFGGLDESLLARAEALAAVDIV
  SQSKSHHHHPPHHSPFKPDATYHTMNTIPCTSAASSSSVPISHPSALAGTHHHHHHHHHH
  HHQPHQALEGELLEHLSPGLALGAMAGPDGAVVSTPAHAPHMATMNPMHQAALSMAHAHG
  LPSHMGCMSDVDADPRDLEAFAERFKQRRIKLGVTQADVGSALANLKIPGVGSLSQSTIC
  RFESLTLSHNNMIALKPILQAWLEEAEKSHREKLTKPELFNGAEKKRKRTSIAAPEKRSL
  EAYFAIQPRPSSEKIAAIAEKLDLKKNVVRVWFCNQRQKQKRMKYSAGI
• Function: Tissue-specific DNA-binding transcription factor involved in the development and differentiation of target cells. Functions either as activator or repressor modulating the rate of target gene transcription through RNA polymerase II enzyme in a promoter-dependent manner. Binds to the consensus octamer motif 5'-AT[A/T]A[T/A]T[A/T]A-3' of promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Binds to an octamer site to form a ternary complex with ISL1; cooperates positively with ISL1 and ISL2 to potentiate transcriptional activation of RGC target genes being involved in RGC fate commitment in the developing retina and RGC axon formation and pathfinding. Inhibits DLX1 and DLX2 transcriptional activities preventing DLX1- and DLX2-mediated ability to promote amacrine cell fate specification. In cooperation with TP53 potentiates transcriptional activation of BAX promoter activity increasing neuronal cell apoptosis. Negatively regulates BAX promoter activity in the absence of TP53. Acts as a transcriptional coactivator via its interaction with the transcription factor ESR1 by enhancing its effect on estrogen response element (ERE)-containing promoter. Antagonizes the transcriptional stimulatory activity of POU4F1 by preventing its binding to an octamer motif. Involved in TNFSF11-mediated terminal osteoclast differentiation.
• Tissue Specificity: Expressed in the brain . Expressed in the ganglion cell layer of the retina .
• Reactome Pathway: Regulation of TP53 Activity through Association with Co-factors (R-HSA-6804759)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[4]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[6]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[5]
Lung cancer	DISCM4YA	moderate	Biomarker	[8]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[8]

3 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 POU domain, class 4, transcription factor 2 (POU4F2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of POU domain, class 4, transcription factor 2 (POU4F2).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of POU domain, class 4, transcription factor 2 (POU4F2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of POU domain, class 4, transcription factor 2 (POU4F2).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of POU domain, class 4, transcription factor 2 (POU4F2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of POU domain, class 4, transcription factor 2 (POU4F2).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of POU domain, class 4, transcription factor 2 (POU4F2).	[14]

References

• [1] Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment.Cell Stress Chaperones. 2011 Jul;16(4):427-39. doi: 10.1007/s12192-011-0256-8. Epub 2011 Jan 29.
• [2] Genome-wide profiling in melatonin-exposed human breast cancer cell lines identifies differentially methylated genes involved in the anticancer effect of melatonin.J Pineal Res. 2013 Jan;54(1):80-8. doi: 10.1111/j.1600-079X.2012.01027.x. Epub 2012 Aug 1.
• [3] An epigenetic biomarker combination of PCDH17 and POU4F2 detects bladder cancer accurately by methylation analyses of urine sediment DNA in Han Chinese.Oncotarget. 2016 Jan 19;7(3):2754-64. doi: 10.18632/oncotarget.6666.
• [4] Predicting the Lung Squamous Cell Carcinoma Diagnosis and Prognosis Markers by Unique DNA Methylation and Gene Expression Profiles.J Comput Biol. 2020 Jul;27(7):1041-1054. doi: 10.1089/cmb.2019.0138. Epub 2019 Nov 11.
• [5] Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells.Oncogene. 2008 Jan 3;27(1):145-54. doi: 10.1038/sj.onc.1210621. Epub 2007 Jul 16.
• [6] Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90.Arthritis Rheum. 2005 Apr;52(4):1171-9. doi: 10.1002/art.21000.
• [7] Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ER and growth factors via MAPK pathway.Breast Cancer Res. 2011 Jan 17;13(1):R5. doi: 10.1186/bcr2809.
• [8] Class III/IV POU transcription factors expressed in small cell lung cancer cells are involved in proneural/neuroendocrine differentiation.Pathol Int. 2014 Sep;64(9):415-22. doi: 10.1111/pin.12198.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] 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.
• [12] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [13] 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.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.