Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK1QUQT)

• DOT Name: Hepatocyte nuclear factor 6 (ONECUT1)
• Synonyms: HNF-6; One cut domain family member 1; One cut homeobox 1
• Gene Name: ONECUT1
• Related Disease:
  Advanced cancer
  Cholangiocarcinoma
  Cholestasis
  Colon carcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Maturity-onset diabetes of the young
  Metastatic malignant neoplasm
  Neoplasm
  Pancreatic cancer
  Pancreatic tumour
  Squamous cell carcinoma
• UniProt ID: HNF6_HUMAN
• Pfam ID: PF02376 ; PF00046
• Sequence:
  MNAQLTMEAIGELHGVSHEPVPAPADLLGGSPHARSSVAHRGSHLPPAHPRSMGMASLLD
  GGSGGGDYHHHHRAPEHSLAGPLHPTMTMACETPPGMSMPTTYTTLTPLQPLPPISTVSD
  KFPHHHHHHHHHHHPHHHQRLAGNVSGSFTLMRDERGLASMNNLYTPYHKDVAGMGQSLS
  PLSSSGLGSIHNSQQGLPHYAHPGAAMPTDKMLTPNGFEAHHPAMLGRHGEQHLTPTSAG
  MVPINGLPPHHPHAHLNAQGHGQLLGTAREPNPSVTGAQVSNGSNSGQMEEINTKEVAQR
  ITTELKRYSIPQAIFAQRVLCRSQGTLSDLLRNPKPWSKLKSGRETFRRMWKWLQEPEFQ
  RMSALRLAACKRKEQEHGKDRGNTPKKPRLVFTDVQRRTLHAIFKENKRPSKELQITISQ
  QLGLELSTVSNFFMNARRRSLDKWQDEGSSNSGNSSSSSSTCTKA
• Function: Transcriptional activator. Binds the consensus sequence 5'-DHWATTGAYTWWD-3' on a variety of gene promoters such as those of HNF3B and TTR. Important for liver genes transcription.
• Tissue Specificity: Highly expressed in liver; lower expression in testis and skin.
• KEGG Pathway:
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Regulation of gene expression in early pancreatic precursor cells (R-HSA-210747)
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[2]
Cholestasis	DISDJJWE	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[7]
Maturity-onset diabetes of the young	DISG75M5	Strong	Genetic Variation	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[7]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[9]
Squamous cell carcinoma	DISQVIFL	moderate	Posttranslational Modification	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Hepatocyte nuclear factor 6 (ONECUT1).	[19]

References

• [1] Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells.PLoS One. 2010 Oct 13;5(10):e13344. doi: 10.1371/journal.pone.0013344.
• [2] Hepatocyte nuclear factor 6 inhibits the growth and metastasis of cholangiocarcinoma cells by regulating miR-122.J Cancer Res Clin Oncol. 2016 May;142(5):969-80. doi: 10.1007/s00432-016-2121-8. Epub 2016 Jan 29.
• [3] Pathophysiologic role of hepatocyte nuclear factor 6.Cell Signal. 2012 Jan;24(1):9-16. doi: 10.1016/j.cellsig.2011.08.009. Epub 2011 Aug 27.
• [4] HNF6 promotes tumor growth in colorectal cancer and enhances liver metastasis in mouse model.J Cell Physiol. 2019 Apr;234(4):3675-3684. doi: 10.1002/jcp.27140. Epub 2018 Sep 7.
• [5] Krppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6.Clin Cancer Res. 2016 Jan 15;22(2):502-12. doi: 10.1158/1078-0432.CCR-15-0528. Epub 2015 Sep 2.
• [6] Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial-mesenchymal transition.J Biol Chem. 2013 Oct 25;288(43):31206-16. doi: 10.1074/jbc.M113.480285. Epub 2013 Sep 10.
• [7] Loss of HNF6 expression correlates with human pancreatic cancer progression.Lab Invest. 2014 May;94(5):517-27. doi: 10.1038/labinvest.2014.47. Epub 2014 Mar 17.
• [8] Mutation screening of the hepatocyte nuclear factor (HNF)-6 gene in Japanese subjects with diabetes mellitus.Diabetes Res Clin Pract. 2001 Jun;52(3):171-4. doi: 10.1016/s0168-8227(01)00222-4.
• [9] Loss of ONECUT1 expression in human pancreatic cancer cells.Oncol Rep. 2008 Jan;19(1):157-63.
• [10] Identification of novel DNA methylation markers in cervical cancer.Int J Cancer. 2008 Jul 1;123(1):161-7. doi: 10.1002/ijc.23519.
• [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] 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.
• [13] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [19] 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.