Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein PKNOX1 (PKNOX1)
• Synonyms: Homeobox protein PREP-1; PBX/knotted homeobox 1
• Gene Name: PKNOX1
• Related Disease:
  Adult lymphoma
  Chromosomal disorder
  Dementia
  Fatty liver disease
  Hyperinsulinemia
  Lung adenocarcinoma
  Lymphoma
  Metabolic disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Pediatric lymphoma
  Retinitis pigmentosa
  Type-1/2 diabetes
  leukaemia
  Leukemia
  Neuroblastoma
• UniProt ID: PKNX1_HUMAN
• PDB ID: 1X2N
• Pfam ID: PF05920 ; PF16493
• Sequence:
  MMATQTLSIDSYQDGQQMQVVTELKTEQDPNCSEPDAEGVSPPPVESQTPMDVDKQAIYR
  HPLFPLLALLFEKCEQSTQGSEGTTSASFDVDIENFVRKQEKEGKPFFCEDPETDNLMVK
  AIQVLRIHLLELEKVNELCKDFCSRYIACLKTKMNSETLLSGEPGSPYSPVQSQQIQSAI
  TGTISPQGIVVPASALQQGNVAMATVAGGTVYQPVTVVTPQGQVVTQTLSPGTIRIQNSQ
  LQLQLNQDLSILHQDDGSSKNKRGVLPKHATNVMRSWLFQHIGHPYPTEDEKKQIAAQTN
  LTLLQVNNWFINARRRILQPMLDSSCSETPKTKKKTAQNRPVQRFWPDSIASGVAQPPPS
  ELTMSEGAVVTITTPVNMNVDSLQSLSSDGATLAVQQVMMAGQSEDESVDSTEEDAGALA
  PAHISGLVLENSDSLQ
• Function: Activates transcription in the presence of PBX1A and HOXA1.
• Tissue Specificity: Ubiquitous. Isoform 2 is expressed in all examined tissues except in bone marrow.
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[1]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[2]
Dementia	DISXL1WY	Strong	Altered Expression	[3]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[4]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[6]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[1]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[1]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[5]
leukaemia	DISS7D1V	moderate	Biomarker	[9]
Leukemia	DISNAKFL	moderate	Biomarker	[9]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Homeobox protein PKNOX1 (PKNOX1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homeobox protein PKNOX1 (PKNOX1).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein PKNOX1 (PKNOX1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeobox protein PKNOX1 (PKNOX1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein PKNOX1 (PKNOX1).	[15]

References

• [1] Prep1 (pKnox1)-deficiency leads to spontaneous tumor development in mice and accelerates EmuMyc lymphomagenesis: a tumor suppressor role for Prep1.Mol Oncol. 2010 Apr;4(2):126-34. doi: 10.1016/j.molonc.2010.01.001. Epub 2010 Jan 7.
• [2] Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability.Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):E314-22. doi: 10.1073/pnas.1105216108. Epub 2011 Jun 29.
• [3] Single nucleotide polymorphism in gene encoding transcription factor Prep1 is associated with HIV-1-associated dementia.PLoS One. 2012;7(2):e30990. doi: 10.1371/journal.pone.0030990. Epub 2012 Feb 7.
• [4] MiR-17 family-mediated regulation of Pknox1 influences hepatic steatosis and insulin signaling.J Cell Mol Med. 2018 Dec;22(12):6167-6175. doi: 10.1111/jcmm.13902. Epub 2018 Oct 19.
• [5] Prep1 deficiency induces protection from diabetes and increased insulin sensitivity through a p160-mediated mechanism.Mol Cell Biol. 2008 Sep;28(18):5634-45. doi: 10.1128/MCB.00117-08. Epub 2008 Jul 21.
• [6] Transcription factor PREP1 induces EMT and metastasis by controlling the TGF--SMAD3 pathway in non-small cell lung adenocarcinoma.Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):E3775-84. doi: 10.1073/pnas.1407074111. Epub 2014 Aug 25.
• [7] PREP1 tumor suppressor protects the late-replicating DNA by controlling its replication timing and symmetry.Sci Rep. 2018 Feb 16;8(1):3198. doi: 10.1038/s41598-018-21363-4.
• [8] Progression of retinitis pigmentosa on multimodal imaging: The PREP-1 study.Clin Exp Ophthalmol. 2019 Jul;47(5):605-613. doi: 10.1111/ceo.13458. Epub 2019 Jan 2.
• [9] The miR-17?2 cluster contributes to MLL leukemia through the repression of MEIS1 competitor PKNOX1.Leuk Res. 2016 Jul;46:51-60. doi: 10.1016/j.leukres.2016.04.006. Epub 2016 Apr 16.
• [10] Overexpression of FABP7 in Down syndrome fetal brains is associated with PKNOX1 gene-dosage imbalance.Nucleic Acids Res. 2003 Jun 1;31(11):2769-77. doi: 10.1093/nar/gkg396.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.