Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT30NFOC)

• DOT Name: POU domain, class 3, transcription factor 2 (POU3F2)
• Synonyms: Brain-specific homeobox/POU domain protein 2; Brain-2; Brn-2; Nervous system-specific octamer-binding transcription factor N-Oct-3; Octamer-binding protein 7; Oct-7; Octamer-binding transcription factor 7; OTF-7
• Gene Name: POU3F2
• Related Disease:
  Adenocarcinoma
  Autism spectrum disorder
  Bipolar depression
  Bipolar disorder
  Carcinoid tumor
  Chromosomal disorder
  Clear cell renal carcinoma
  Intellectual disability
  Lung adenocarcinoma
  Lung neoplasm
  Lung squamous cell carcinoma
  Melanoma
  Mental disorder
  Metastatic malignant neoplasm
  Microphthalmia
  Multiple endocrine neoplasia type 1
  Neoplasm
  Obesity
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Small-cell lung cancer
  Lung cancer
  Schizophrenia
• UniProt ID: PO3F2_HUMAN
• PDB ID: 7XRC
• Pfam ID: PF00046 ; PF00157
• Sequence:
  MATAASNHYSLLTSSASIVHAEPPGGMQQGAGGYREAQSLVQGDYGALQSNGHPLSHAHQ
  WITALSHGGGGGGGGGGGGGGGGGGGGGDGSPWSTSPLGQPDIKPSVVVQQGGRGDELHG
  PGALQQQHQQQQQQQQQQQQQQQQQQQQQRPPHLVHHAANHHPGPGAWRSAAAAAHLPPS
  MGASNGGLLYSQPSFTVNGMLGAGGQPAGLHHHGLRDAHDEPHHADHHPHPHSHPHQQPP
  PPPPPQGPPGHPGAHHDPHSDEDTPTSDDLEQFAKQFKQRRIKLGFTQADVGLALGTLYG
  NVFSQTTICRFEALQLSFKNMCKLKPLLNKWLEEADSSSGSPTSIDKIAAQGRKRKKRTS
  IEVSVKGALESHFLKCPKPSAQEITSLADSLQLEKEVVRVWFCNRRQKEKRMTPPGGTLP
  GAEDVYGGSRDTPPHHGVQTPVQ
• Function: Transcription factor that plays a key role in neuronal differentiation. Binds preferentially to the recognition sequence which consists of two distinct half-sites, ('GCAT') and ('TAAT'), separated by a non-conserved spacer region of 0, 2, or 3 nucleotides. Acts as a transcriptional activator when binding cooperatively with SOX4, SOX11, or SOX12 to gene promoters. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Acts downstream of ASCL1, accessing chromatin that has been opened by ASCL1, and promotes transcription of neuronal genes.
• Tissue Specificity: Expressed specifically in the neuroectodermal cell lineage.
• Reactome Pathway: EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[2]
Bipolar depression	DISA75FU	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Carcinoid tumor	DISMNRDC	Strong	Altered Expression	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[9]
Lung neoplasm	DISVARNB	Strong	Biomarker	[9]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[10]
Melanoma	DIS1RRCY	Strong	Biomarker	[11]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[12]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[13]
Microphthalmia	DISGEBES	Strong	Altered Expression	[14]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Genetic Variation	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[7]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	moderate	Biomarker	[18]
Schizophrenia	DISSRV2N	Limited	Biomarker	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	POU domain, class 3, transcription factor 2 (POU3F2) increases the response to substance of (+)-JQ1.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of POU domain, class 3, transcription factor 2 (POU3F2).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of POU domain, class 3, transcription factor 2 (POU3F2).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of POU domain, class 3, transcription factor 2 (POU3F2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of POU domain, class 3, transcription factor 2 (POU3F2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of POU domain, class 3, transcription factor 2 (POU3F2).	[24]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of POU domain, class 3, transcription factor 2 (POU3F2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of POU domain, class 3, transcription factor 2 (POU3F2).	[23]

References

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• [2] RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders.PLoS One. 2011;6(9):e23356. doi: 10.1371/journal.pone.0023356. Epub 2011 Sep 7.
• [3] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [4] Genome-Scale Transcriptional Regulatory Network Models of Psychiatric and Neurodegenerative Disorders.Cell Syst. 2019 Feb 27;8(2):122-135.e7. doi: 10.1016/j.cels.2019.01.002. Epub 2019 Feb 13.
• [5] Expression of developing neural transcription factors in lung carcinoid tumors.Pathol Int. 2014 Aug;64(8):365-74. doi: 10.1111/pin.12183.
• [6] The brn-2 gene regulates the melanocytic phenotype and tumorigenic potential of human melanoma cells.Oncogene. 1995 Aug 17;11(4):691-700.
• [7] Analysis of the regulation of fatty acid binding protein 7 expression in human renal carcinoma cell lines.BMC Mol Biol. 2011 Jul 19;12:31. doi: 10.1186/1471-2199-12-31.
• [8] Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.Am J Hum Genet. 2016 Feb 4;98(2):363-72. doi: 10.1016/j.ajhg.2015.12.014. Epub 2016 Jan 28.
• [9] Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer.Lab Invest. 2013 Apr;93(4):408-21. doi: 10.1038/labinvest.2013.2. Epub 2013 Jan 28.
• [10] Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma.Cancer Res. 2019 Dec 15;79(24):6084-6100. doi: 10.1158/0008-5472.CAN-19-2132. Epub 2019 Sep 24.
• [11] BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma.Genes Dev. 2019 Mar 1;33(5-6):310-332. doi: 10.1101/gad.314633.118. Epub 2019 Feb 25.
• [12] The transcription factor POU3F2 regulates a gene coexpression network in brain tissue from patients with psychiatric disorders.Sci Transl Med. 2018 Dec 19;10(472):eaat8178. doi: 10.1126/scitranslmed.aat8178. Epub 2018 Dec 13.
• [13] Visualization of the metastatic process by green fluorescent protein expression.Anticancer Res. 1997 Jul-Aug;17(4A):2377-84.
• [14] Epithelial-mesenchymal-transition-like and TGF pathways associated with autochthonous inflammatory melanoma development in mice.PLoS One. 2012;7(11):e49419. doi: 10.1371/journal.pone.0049419. Epub 2012 Nov 16.
• [15] BRN2, a POUerful driver of melanoma phenotype switching and metastasis.Pigment Cell Melanoma Res. 2019 Jan;32(1):9-24. doi: 10.1111/pcmr.12710. Epub 2018 Jun 5.
• [16] Clinical and molecular features of treatment-related neuroendocrine prostate cancer.Int J Urol. 2018 Apr;25(4):345-351. doi: 10.1111/iju.13526. Epub 2018 Feb 3.
• [17] Immunohistochemical study of the neural development transcription factors (TTF1, ASCL1 and BRN2) in neuroendocrine prostate tumours.Actas Urol Esp. 2017 Oct;41(8):529-534. doi: 10.1016/j.acuro.2016.11.009. Epub 2017 Mar 9.
• [18] 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.
• [19] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] 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.
• [24] 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.
• [25] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [26] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.