Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILD0XS)

• DOT Name: POU domain, class 4, transcription factor 3 (POU4F3)
• Synonyms: Brain-specific homeobox/POU domain protein 3C; Brain-3C; Brn-3C
• Gene Name: POU4F3
• Related Disease:
  Nonsyndromic genetic hearing loss
  Wolfram syndrome
  Advanced cancer
  Autosomal dominant nonsyndromic hearing loss 15
  Classic Hodgkin lymphoma
  Dysplasia of cervix
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Lung cancer
  Sensorineural hearing loss disorder
  Small-cell lung cancer
  Autosomal dominant nonsyndromic hearing loss
• UniProt ID: PO4F3_HUMAN
• Pfam ID: PF00046 ; PF00157
• Sequence:
  MMAMNSKQPFGMHPVLQEPKFSSLHSGSEAMRRVCLPAPQLQGNIFGSFDESLLARAEAL
  AAVDIVSHGKNHPFKPDATYHTMSSVPCTSTSSTVPISHPAALTSHPHHAVHQGLEGDLL
  EHISPTLSVSGLGAPEHSVMPAQIHPHHLGAMGHLHQAMGMSHPHTVAPHSAMPACLSDV
  ESDPRELEAFAERFKQRRIKLGVTQADVGAALANLKIPGVGSLSQSTICRFESLTLSHNN
  MIALKPVLQAWLEEAEAAYREKNSKPELFNGSERKRKRTSIAAPEKRSLEAYFAIQPRPS
  SEKIAAIAEKLDLKKNVVRVWFCNQRQKQKRMKYSAVH
• Function: Acts as a transcriptional activator. Acts by binding to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes. Involved in the auditory system development, required for terminal differentiation of hair cells in the inner ear.
• Tissue Specificity: Brain. Seems to be specific to the retina.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[1]
Wolfram syndrome	DISN16XW	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autosomal dominant nonsyndromic hearing loss 15	DISJPU4M	Strong	Autosomal dominant	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[5]
Dysplasia of cervix	DISOAROS	Strong	Biomarker	[3]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[6]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	moderate	Biomarker	[8]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Biomarker	[9]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[8]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[10]

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 3 (POU4F3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of POU domain, class 4, transcription factor 3 (POU4F3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of POU domain, class 4, transcription factor 3 (POU4F3).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] DFNA54, a third locus for low-frequency hearing loss.J Mol Med (Berl). 2004 Nov;82(11):775-80. doi: 10.1007/s00109-004-0597-1. Epub 2004 Oct 13.
• [3] Performance of a new HPV and biomarker assay in the management of hrHPV positive women: Subanalysis of the ongoing multicenter TRACE clinical trial (n??,000) to evaluate POU4F3 methylation as a potential biomarker of cervical precancer and cancer.Int J Cancer. 2017 Mar 1;140(5):1119-1133. doi: 10.1002/ijc.30534.
• [4] Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding. Hum Mutat. 2008 Apr;29(4):545-54. doi: 10.1002/humu.20693.
• [5] POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.PLoS One. 2017 May 17;12(5):e0177636. doi: 10.1371/journal.pone.0177636. eCollection 2017.
• [6] The feasibility of detecting endometrial and ovarian cancer using DNA methylation biomarkers in cervical scrapings.J Gynecol Oncol. 2018 Jan;29(1):e17. doi: 10.3802/jgo.2018.29.e17.
• [7] Brn-3a neuronal transcription factor functional expression in human prostate cancer.Prostate Cancer Prostatic Dis. 2006;9(1):83-91. doi: 10.1038/sj.pcan.4500837.
• [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] Bioinformatics analysis of candidate genes and mutations in a congenital sensorineural hearing loss pedigree: detection of 52 genes for the DFNA52 locus.J Laryngol Otol. 2008 Oct;122(10):1029-36. doi: 10.1017/S0022215107001582. Epub 2008 Feb 29.
• [10] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [11] 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.
• [12] 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.
• [13] 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.