Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHUE5YY)

• DOT Name: One cut domain family member 2 (ONECUT2)
• Synonyms: Hepatocyte nuclear factor 6-beta; HNF-6-beta; One cut homeobox 2; Transcription factor ONECUT-2; OC-2
• Gene Name: ONECUT2
• Related Disease:
  B-cell neoplasm
  Prostate neoplasm
  Advanced cancer
  Brain neoplasm
  Neuroendocrine neoplasm
  Non-small-cell lung cancer
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Waardenburg syndrome
  Neoplasm
  Colorectal carcinoma
• UniProt ID: ONEC2_HUMAN
• Pfam ID: PF02376 ; PF00046
• Sequence:
  MKAAYTAYRCLTKDLEGCAMNPELTMESLGTLHGPAGGGSGGGGGGGGGGGGGGPGHEQE
  LLASPSPHHAGRGAAGSLRGPPPPPTAHQELGTAAAAAAAASRSAMVTSMASILDGGDYR
  PELSIPLHHAMSMSCDSSPPGMGMSNTYTTLTPLQPLPPISTVSDKFHHPHPHHHPHHHH
  HHHHQRLSGNVSGSFTLMRDERGLPAMNNLYSPYKEMPGMSQSLSPLAATPLGNGLGGLH
  NAQQSLPNYGPPGHDKMLSPNFDAHHTAMLTRGEQHLSRGLGTPPAAMMSHLNGLHHPGH
  TQSHGPVLAPSRERPPSSSSGSQVATSGQLEEINTKEVAQRITAELKRYSIPQAIFAQRV
  LCRSQGTLSDLLRNPKPWSKLKSGRETFRRMWKWLQEPEFQRMSALRLAACKRKEQEPNK
  DRNNSQKKSRLVFTDLQRRTLFAIFKENKRPSKEMQITISQQLGLELTTVSNFFMNARRR
  SLEKWQDDLSTGGSSSTSSTCTKA
• Function: Transcriptional activator. Activates the transcription of a number of liver genes such as HNF3B.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Posttranslational Modification	[1]
Prostate neoplasm	DISHDKGQ	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Waardenburg syndrome	DISRU41A	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[9]

11 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 One cut domain family member 2 (ONECUT2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of One cut domain family member 2 (ONECUT2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of One cut domain family member 2 (ONECUT2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of One cut domain family member 2 (ONECUT2).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of One cut domain family member 2 (ONECUT2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of One cut domain family member 2 (ONECUT2).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of One cut domain family member 2 (ONECUT2).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of One cut domain family member 2 (ONECUT2).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of One cut domain family member 2 (ONECUT2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of One cut domain family member 2 (ONECUT2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of One cut domain family member 2 (ONECUT2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of One cut domain family member 2 (ONECUT2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of One cut domain family member 2 (ONECUT2).	[19]

References

• [1] DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status.Leukemia. 2008 May;22(5):1035-43. doi: 10.1038/leu.2008.18. Epub 2008 Feb 21.
• [2] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [3] Chemotherapy-Induced Extracellular Vesicle miRNAs Promote Breast Cancer Stemness by Targeting ONECUT2.Cancer Res. 2019 Jul 15;79(14):3608-3621. doi: 10.1158/0008-5472.CAN-18-4055. Epub 2019 May 22.
• [4] Identification of transcriptional regulatory networks specific to pilocytic astrocytoma.BMC Med Genomics. 2011 Jul 11;4:57. doi: 10.1186/1755-8794-4-57.
• [5] ONECUT2 is a driver of neuroendocrine prostate cancer.Nat Commun. 2019 Jan 17;10(1):278. doi: 10.1038/s41467-018-08133-6.
• [6] THUMPD3-AS1 Is Correlated With Non-Small Cell Lung Cancer And Regulates Self-Renewal Through miR-543 And ONECUT2.Onco Targets Ther. 2019 Nov 19;12:9849-9860. doi: 10.2147/OTT.S227995. eCollection 2019.
• [7] The transcription factor onecut-2 controls the microphthalmia-associated transcription factor gene.Biochem Biophys Res Commun. 2001 Aug 3;285(5):1200-5. doi: 10.1006/bbrc.2001.5294.
• [8] Blockade of ONECUT2 expression in ovarian cancer inhibited tumor cell proliferation, migration, invasion and angiogenesis.Cancer Sci. 2018 Jul;109(7):2221-2234. doi: 10.1111/cas.13633. Epub 2018 Jun 13.
• [9] Next-generation sequencing analysis of multiplex families with atypical psychosis.Transl Psychiatry. 2018 Oct 15;8(1):221. doi: 10.1038/s41398-018-0272-x.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] 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.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [22] 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.