Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9DOUKL)

• DOT Name: Hepatocyte nuclear factor 1-alpha (HNF1A)
• Synonyms: HNF-1-alpha; HNF-1A; Liver-specific transcription factor LF-B1; LFB1; Transcription factor 1; TCF-1
• Gene Name: HNF1A
• Related Disease:
  Monogenic diabetes
  Type 1 diabetes mellitus 20
  Maturity-onset diabetes of the young type 3
  Obsolete diabetes mellitus, noninsulin-dependent
  Hyperinsulinism due to HNF1A deficiency
  Maturity-onset diabetes of the young
  Nonpapillary renal cell carcinoma
• UniProt ID: HNF1A_HUMAN
• PDB ID: 1IC8; 2GYP
• Pfam ID: PF04814 ; PF04813 ; PF04812
• Sequence:
  MVSKLSQLQTELLAALLESGLSKEALIQALGEPGPYLLAGEGPLDKGESCGGGRGELAEL
  PNGLGETRGSEDETDDDGEDFTPPILKELENLSPEEAAHQKAVVETLLQEDPWRVAKMVK
  SYLQQHNIPQREVVDTTGLNQSHLSQHLNKGTPMKTQKRAALYTWYVRKQREVAQQFTHA
  GQGGLIEEPTGDELPTKKGRRNRFKWGPASQQILFQAYERQKNPSKEERETLVEECNRAE
  CIQRGVSPSQAQGLGSNLVTEVRVYNWFANRRKEEAFRHKLAMDTYSGPPPGPGPGPALP
  AHSSPGLPPPALSPSKVHGVRYGQPATSETAEVPSSSGGPLVTVSTPLHQVSPTGLEPSH
  SLLSTEAKLVSAAGGPLPPVSTLTALHSLEQTSPGLNQQPQNLIMASLPGVMTIGPGEPA
  SLGPTFTNTGASTLVIGLASTQAQSVPVINSMGSSLTTLQPVQFSQPLHPSYQQPLMPPV
  QSHVTQSPFMATMAQLQSPHALYSHKPEVAQYTHTGLLPQTMLITDTTNLSALASLTPTK
  QVFTSDTEASSESGLHTPASQATTLHVPSQDPAGIQHLQPAHRLSASPTVSSSSLVLYQS
  SDSSNGQSHLLPSNHSVIETFISTQMASSSQ
• Function: Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver. Binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Activates the transcription of CYP1A2, CYP2E1 and CYP3A11; (Microbial infection) Plays a crucial role for hepatitis B virus gene transcription and DNA replication. Mechanistically, synergistically cooperates with NR5A2 to up-regulate the activity of one of the critical cis-elements in the hepatitis B virus genome enhancer II (ENII).
• Tissue Specificity: Liver.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway: Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Monogenic diabetes	DISEB8Q0	Definitive	Autosomal dominant	[1]
Type 1 diabetes mellitus 20	DIS7X7T1	Definitive	Autosomal dominant	[2]
Maturity-onset diabetes of the young type 3	DISMFSO5	Strong	Autosomal dominant	[2]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Strong	Autosomal dominant	[2]
Hyperinsulinism due to HNF1A deficiency	DISO3TTI	Supportive	Autosomal dominant	[3]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[4]
Nonpapillary renal cell carcinoma	DISGFURW	No Known	Unknown	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	Hepatocyte nuclear factor 1-alpha (HNF1A) affects the response to substance of D-glucose.	[22]

15 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 1-alpha (HNF1A).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[10]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[16]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[19]
Baicalin	DMY1TLZ	Terminated	Baicalin decreases the expression of Hepatocyte nuclear factor 1-alpha (HNF1A).	[21]

2 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 decreases the methylation of Hepatocyte nuclear factor 1-alpha (HNF1A).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Hepatocyte nuclear factor 1-alpha (HNF1A).	[20]

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] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012 Oct;97(10):E2026-30. doi: 10.1210/jc.2012-1356. Epub 2012 Jul 16.
• [4] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [5] Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Hum Mol Genet. 2005 Mar 1;14(5):603-14. doi: 10.1093/hmg/ddi057. Epub 2005 Jan 13.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [11] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [12] Salvianolic acid B protects against chronic alcoholic liver injury via SIRT1-mediated inhibition of CRP and ChREBP in rats. Toxicol Lett. 2017 Feb 5;267:1-10. doi: 10.1016/j.toxlet.2016.12.010. Epub 2016 Dec 15.
• [13] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [14] Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9. J Hematol Oncol. 2015 May 8;8:46. doi: 10.1186/s13045-015-0143-3.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism. J Biol Chem. 2011 Feb 25;286(8):6049-60. doi: 10.1074/jbc.M110.176842. Epub 2010 Dec 16.
• [17] Thymoquinone suppresses invasion and metastasis in bladder cancer cells by reversing EMT through the Wnt/-catenin signaling pathway. Chem Biol Interact. 2020 Apr 1;320:109022. doi: 10.1016/j.cbi.2020.109022. Epub 2020 Feb 27.
• [18] 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.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Baicalin down-regulating hepatitis B virus transcription depends on the liver-specific HNF4-HNF1 axis. Toxicol Appl Pharmacol. 2020 Sep 15;403:115131. doi: 10.1016/j.taap.2020.115131. Epub 2020 Jul 17.
• [22] Preserved insulin response to tolbutamide in hepatocyte nuclear factor-1alpha mutation carriers. Diabet Med. 2005 Apr;22(4):406-9. doi: 10.1111/j.1464-5491.2005.01439.x.