Details of Drug Off-Target (DOT)

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

• DOT Name: POU domain, class 4, transcription factor 1 (POU4F1)
• Synonyms: Brain-specific homeobox/POU domain protein 3A; Brain-3A; Brn-3A; Homeobox/POU domain protein RDC-1; Oct-T1
• Gene Name: POU4F1
• Related Disease:
  Acute monocytic leukemia
  Advanced cancer
  Ataxia, intention tremor, and hypotonia syndrome, childhood-onset
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Cervix disorder
  Chromosomal disorder
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Malignant soft tissue neoplasm
  Medulloblastoma
  Neuroblastoma
  Neuronal ceroid lipofuscinosis
  Non-arteritic anterior ischemic optic neuropathy
  Ocular hypertension
  Pheochromocytoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Sarcoma
  Systemic lupus erythematosus
  Vibrio cholerae infection
  Melanoma
  Rhabdomyosarcoma
  Type-1/2 diabetes
  Acute myelogenous leukaemia
  Uterine cervix neoplasm
• UniProt ID: PO4F1_HUMAN
• Pfam ID: PF00046 ; PF00157
• Sequence:
  MMSMNSKQPHFAMHPTLPEHKYPSLHSSSEAIRRACLPTPPLQSNLFASLDETLLARAEA
  LAAVDIAVSQGKSHPFKPDATYHTMNSVPCTSTSTVPLAHHHHHHHHHQALEPGDLLDHI
  SSPSLALMAGAGGAGAAAGGGGAHDGPGGGGGPGGGGGPGGGPGGGGGGGPGGGGGGPGG
  GLLGGSAHPHPHMHSLGHLSHPAAAAAMNMPSGLPHPGLVAAAAHHGAAAAAAAAAAGQV
  AAASAAAAVVGAAGLASICDSDTDPRELEAFAERFKQRRIKLGVTQADVGSALANLKIPG
  VGSLSQSTICRFESLTLSHNNMIALKPILQAWLEEAEGAQREKMNKPELFNGGEKKRKRT
  SIAAPEKRSLEAYFAVQPRPSSEKIAAIAEKLDLKKNVVRVWFCNQRQKQKRMKFSATY
• Function: Multifunctional transcription factor with different regions mediating its different effects. Acts by binding (via its C-terminal domain) to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes. Regulates the expression of specific genes involved in differentiation and survival within a subset of neuronal lineages. It has been shown that activation of some of these genes requires its N-terminal domain, maybe through a neuronal-specific cofactor. Ativates BCL2 expression and protects neuronal cells from apoptosis (via the N-terminal domain). Induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. Exerts its major developmental effects in somatosensory neurons and in brainstem nuclei involved in motor control. Stimulates the binding affinity of the nuclear estrogene receptor ESR1 to DNA estrogen response element (ERE), and hence modulates ESR1-induced transcriptional activity. May positively regulate POU4F2 and POU4F3. Regulates dorsal root ganglion sensory neuron specification and axonal projection into the spinal cord. Plays a role in TNFSF11-mediated terminal osteoclast differentiation. Negatively regulates its own expression interacting directly with a highly conserved autoregulatory domain surrounding the transcription initiation site; [Isoform 2]: Able to act as transcription factor, cannot regulate the expression of the same subset of genes than isoform 1. Does not have antiapoptotic effect on neuronal cells.
• Tissue Specificity: Expressed in the brain and the retina. Present in the developing brain, spinal cord and eye.
• Reactome Pathway: Regulation of TP53 Activity through Association with Co-factors (R-HSA-6804759)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Ataxia, intention tremor, and hypotonia syndrome, childhood-onset	DISK8R72	Strong	Autosomal dominant	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[2]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[2]
Cervix disorder	DIS1HG31	Strong	Biomarker	[5]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[8]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[9]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[10]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Strong	Genetic Variation	[11]
Non-arteritic anterior ischemic optic neuropathy	DIS53TUF	Strong	Biomarker	[12]
Ocular hypertension	DISC2BT9	Strong	Biomarker	[13]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[14]
Prostate cancer	DISF190Y	Strong	Altered Expression	[15]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[15]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[15]
Sarcoma	DISZDG3U	Strong	Altered Expression	[8]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[16]
Vibrio cholerae infection	DISW7E3U	Strong	Altered Expression	[17]
Melanoma	DIS1RRCY	moderate	Altered Expression	[18]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[10]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[19]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Altered Expression	[20]
Uterine cervix neoplasm	DIS0BYVV	Limited	Biomarker	[4]

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 1 (POU4F1).	[21]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of POU domain, class 4, transcription factor 1 (POU4F1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of POU domain, class 4, transcription factor 1 (POU4F1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[25]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[27]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[28]
Marinol	DM70IK5	Approved	Marinol decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[34]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of POU domain, class 4, transcription factor 1 (POU4F1).	[35]

References

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• [9] Novel Brn3a cis-acting sequences mediate transcription of human trkA in neurons.J Neurochem. 2008 Apr;105(2):425-35. doi: 10.1111/j.1471-4159.2007.05139.x. Epub 2007 Dec 12.
• [10] EWS/ETS proteins promote expression and regulate function of the homeodomain transcription factor BRN3A.Oncogene. 2010 May 27;29(21):3134-45. doi: 10.1038/onc.2010.72. Epub 2010 Mar 29.
• [11] The Brn-3a transcription factor gene (POU4F1) maps close to the locus for the variant late infantile form of neuronal ceroid-lipofuscinosis.Cytogenet Cell Genet. 1996;74(3):225-6. doi: 10.1159/000134422.
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• [16] Heat shock protein 27 and its regulatory molecules express differentially in SLE patients with distinct autoantibody profiles.Immunol Lett. 2015 Mar;164(1):25-32. doi: 10.1016/j.imlet.2015.01.007. Epub 2015 Feb 2.
• [17] Cell type-specific expression of FoxP2 in the ferret and mouse retina.Neurosci Res. 2017 Apr;117:1-13. doi: 10.1016/j.neures.2016.11.008. Epub 2016 Nov 22.
• [18] The lncRNA SLNCR1 Mediates Melanoma Invasion through a Conserved SRA1-like Region.Cell Rep. 2016 May 31;15(9):2025-37. doi: 10.1016/j.celrep.2016.04.018. Epub 2016 May 19.
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• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
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• [33] 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.
• [34] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [35] 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.