Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHJ8WTU)

DOT Name Potassium voltage-gated channel subfamily H member 4 (KCNH4)
Synonyms Brain-specific eag-like channel 2; BEC2; Ether-a-go-go-like potassium channel 1; ELK channel 1; ELK1; Voltage-gated potassium channel subunit Kv12.3
Gene Name KCNH4
Related Disease
Neuroblastoma ( )
Acute myelogenous leukaemia ( )
Alzheimer disease ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Breast adenocarcinoma ( )
Breast cancer ( )
Breast carcinoma ( )
Breast neoplasm ( )
Depression ( )
Esophageal cancer ( )
Esophageal squamous cell carcinoma ( )
Fibrosarcoma ( )
Hepatocellular carcinoma ( )
Huntington disease ( )
Insulinoma ( )
Melanoma ( )
Neoplasm of esophagus ( )
Non-small-cell lung cancer ( )
Premature aging syndrome ( )
Primary sclerosing cholangitis ( )
Prostate cancer ( )
Prostate carcinoma ( )
Pulmonary arterial hypertension ( )
Renal cell carcinoma ( )
Synovial sarcoma ( )
Systemic lupus erythematosus ( )
Triple negative breast cancer ( )
Adult glioblastoma ( )
Carcinoma of liver and intrahepatic biliary tract ( )
Glioblastoma multiforme ( )
Liver cancer ( )
Lung cancer ( )
Small-cell lung cancer ( )
Bladder transitional cell carcinoma ( )
Tarsal-carpal coalition syndrome ( )
Familial medullary thyroid carcinoma ( )
Lewy body dementia ( )
UniProt ID
KCNH4_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
Pfam ID
PF00520 ; PF13426
Sequence
MPVMKGLLAPQNTFLDTIATRFDGTHSNFLLANAQGTRGFPIVYCSDGFCELTGYGRTEV
MQKTCSCRFLYGPETSEPALQRLHKALEGHQEHRAEICFYRKDGSAFWCLLDMMPIKNEM
GEVVLFLFSFKDITQSGSPGLGPQGGRGDSNHENSLGRRGATWKFRSARRRSRTVLHRLT
GHFGRRGQGGMKANNNVFEPKPSVPEYKVASVGGSRCLLLHYSVSKAIWDGLILLATFYV
AVTVPYNVCFSGDDDTPITSRHTLVSDIAVEMLFILDIILNFRTTYVSQSGQVISAPRSI
GLHYLATWFFIDLIAALPFDLLYIFNITVTSLVHLLKTVRLLRLLRLLQKLERYSQCSAV
VLTLLMSVFALLAHWMACIWYVIGRREMEANDPLLWDIGWLHELGKRLEVPYVNGSVGGP
SRRSAYIAALYFTLSSLTSVGFGNVCANTDAEKIFSICTMLIGALMHAVVFGNVTAIIQR
MYSRRSLYHSRMKDLKDFIRVHRLPRPLKQRMLEYFQTTWAVNSGIDANELLRDFPDELR
ADIAMHLNREILQLPLFGAASRGCLRALSLHIKTSFCAPGEYLLRRGDALQAHYYVCSGS
LEVLRDNMVLAILGKGDLIGADIPEPGQEPGLGADPNFVLKTSADVKALTYCGLQQLSSR
GLAEVLRLYPEYGAAFRAGLPRDLTFNLRQGSDTSGLSRFSRSPRLSQPRSESLGSSSDK
TLPSITEAESGAEPGGGPRPRRPLLLPNLSPARPRGSLVSLLGEELPPFSALVSSPSLSP
SLSPALAGQGHSASPHGPPRCSAAWKPPQLLIPPLGTFGPPDLSPRIVDGIEDSGSTAEA
PSFRFSRRPELPRPRSQAPPTGTRPSPELASEAEEVKEKVCRLNQEISRLNQEVSQLSRE
LRHIMGLLQARLGPPGHPAGSAWTPDPPCPQLRPPCLSPCASRPPPSLQDTTLAEVHCPA
SVGTMETGTALLDLRPSILPPYPSEPDPLGPSPVPEASPPTPSLLRHSFQSRSDTFH
Function Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits an outward current, but shows no inactivation. Channel properties may be modulated by cAMP and subunit assembly.
Tissue Specificity Detected only in brain, in particular in the telencephalon. Detected in putamen and caudate nucleus, and at lower levels in cerebral cortex, occipital and hippocampus.
Reactome Pathway
Voltage gated Potassium channels (R-HSA-1296072 )

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neuroblastoma DISVZBI4 Definitive Biomarker [1]
Acute myelogenous leukaemia DISCSPTN Strong Altered Expression [2]
Alzheimer disease DISF8S70 Strong Biomarker [3]
Arteriosclerosis DISK5QGC Strong Altered Expression [4]
Atherosclerosis DISMN9J3 Strong Altered Expression [4]
Breast adenocarcinoma DISMPHJ0 Strong Altered Expression [5]
Breast cancer DIS7DPX1 Strong Altered Expression [6]
Breast carcinoma DIS2UE88 Strong Altered Expression [6]
Breast neoplasm DISNGJLM Strong Biomarker [7]
Depression DIS3XJ69 Strong Biomarker [8]
Esophageal cancer DISGB2VN Strong Altered Expression [9]
Esophageal squamous cell carcinoma DIS5N2GV Strong Altered Expression [9]
Fibrosarcoma DISWX7MU Strong Altered Expression [10]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [11]
Huntington disease DISQPLA4 Strong Biomarker [12]
Insulinoma DISIU1JS Strong Altered Expression [13]
Melanoma DIS1RRCY Strong Biomarker [14]
Neoplasm of esophagus DISOLKAQ Strong Altered Expression [9]
Non-small-cell lung cancer DIS5Y6R9 Strong Genetic Variation [15]
Premature aging syndrome DIS51AGT Strong Altered Expression [16]
Primary sclerosing cholangitis DISTH5WJ Strong Altered Expression [17]
Prostate cancer DISF190Y Strong Altered Expression [18]
Prostate carcinoma DISMJPLE Strong Altered Expression [18]
Pulmonary arterial hypertension DISP8ZX5 Strong Altered Expression [19]
Renal cell carcinoma DISQZ2X8 Strong Biomarker [20]
Synovial sarcoma DISEZJS7 Strong Biomarker [20]
Systemic lupus erythematosus DISI1SZ7 Strong Biomarker [21]
Triple negative breast cancer DISAMG6N Strong Altered Expression [22]
Adult glioblastoma DISVP4LU moderate Altered Expression [23]
Carcinoma of liver and intrahepatic biliary tract DIS8WA0W moderate Biomarker [24]
Glioblastoma multiforme DISK8246 moderate Altered Expression [23]
Liver cancer DISDE4BI moderate Biomarker [24]
Lung cancer DISCM4YA moderate Altered Expression [11]
Small-cell lung cancer DISK3LZD moderate Biomarker [25]
Bladder transitional cell carcinoma DISNL46A Disputed Altered Expression [26]
Tarsal-carpal coalition syndrome DISY90L2 Disputed Altered Expression [26]
Familial medullary thyroid carcinoma DIS01PWX Limited Genetic Variation [27]
Lewy body dementia DISAE66J Limited Biomarker [28]
------------------------------------------------------------------------------------
⏷ Show the Full List of 38 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Potassium voltage-gated channel subfamily H member 4 (KCNH4). [29]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily H member 4 (KCNH4). [32]
------------------------------------------------------------------------------------
2 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin increases the expression of Potassium voltage-gated channel subfamily H member 4 (KCNH4). [30]
Ivermectin DMDBX5F Approved Ivermectin increases the expression of Potassium voltage-gated channel subfamily H member 4 (KCNH4). [31]
------------------------------------------------------------------------------------

References

1 Elk-1 interacts with neuronal microtubules and relocalizes to the nucleus upon phosphorylation.Mol Cell Neurosci. 2009 Jan;40(1):111-9. doi: 10.1016/j.mcn.2008.10.004. Epub 2008 Oct 28.
2 Genome-wide characterization of lncRNAs in acute myeloid leukemia.Brief Bioinform. 2018 Jul 20;19(4):627-635. doi: 10.1093/bib/bbx007.
3 Protein inhibitor of activated STAT1 Ser(503) phosphorylation-mediated Elk-1 SUMOylation promotes neuronal survival in APP/PS1 mice.Br J Pharmacol. 2019 Jun;176(11):1793-1810. doi: 10.1111/bph.14656. Epub 2019 Apr 24.
4 Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress.Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1420-5. doi: 10.1073/pnas.0237367100. Epub 2003 Jan 13.
5 Epidermal growth factor regulates PAI-1 expression via activation of the transcription factor Elk-1.Biochim Biophys Acta. 2010 Sep;1799(9):616-21. doi: 10.1016/j.bbagrm.2010.08.004. Epub 2010 Aug 19.
6 15-Deoxy-12,14-prostaglandin J2 induces expression of 15-hydroxyprostaglandin dehydrogenase through Elk-1 activation in human breast cancer MDA-MB-231 cells.Mutat Res. 2014 Oct;768:6-15. doi: 10.1016/j.mrfmmm.2014.06.005. Epub 2014 Jun 24.
7 A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer.Neoplasia. 2011 Feb;13(2):154-66. doi: 10.1593/neo.101324.
8 Antidepressive effects of targeting ELK-1 signal transduction.Nat Med. 2018 May;24(5):591-597. doi: 10.1038/s41591-018-0011-0. Epub 2018 May 7.
9 Overexpression of Ets-like protein 1 in human esophageal squamous cell carcinoma.World J Gastroenterol. 2006 Dec 28;12(48):7859-63. doi: 10.3748/wjg.v12.i48.7859.
10 Induction of early growth response-1 gene expression by calmodulin antagonist trifluoperazine through the activation of Elk-1 in human fibrosarcoma HT1080 cells.J Biol Chem. 2001 Mar 16;276(11):7797-805. doi: 10.1074/jbc.M009465200. Epub 2000 Dec 19.
11 MZF-1/Elk-1/PKC is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma.J Cancer. 2017 Sep 2;8(15):3028-3036. doi: 10.7150/jca.20467. eCollection 2017.
12 Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington's disease.Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24840-24851. doi: 10.1073/pnas.1908113116. Epub 2019 Nov 19.
13 Activation of Elk-1, an Ets transcription factor, by glucose and EGF treatment of insulinoma cells.Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1286-99. doi: 10.1152/ajpendo.2001.281.6.E1286.
14 Immunization of melanoma patients with BEC2 anti-idiotypic monoclonal antibody that mimics GD3 ganglioside: enhanced immunogenicity when combined with adjuvant.Clin Cancer Res. 1996 Apr;2(4):679-86.
15 Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A.Oncotarget. 2015 Feb 10;6(4):2164-79. doi: 10.18632/oncotarget.2941.
16 Reduced phosphorylation of transcription factor Elk-1 in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance.Exp Clin Endocrinol Diabetes. 2005 Feb;113(2):94-101. doi: 10.1055/s-2004-830554.
17 Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis.Gastroenterology. 2007 Apr;132(4):1504-14. doi: 10.1053/j.gastro.2007.01.039. Epub 2007 Jan 25.
18 GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells.Regul Pept. 2002 Nov 15;109(1-3):141-8. doi: 10.1016/s0167-0115(02)00197-0.
19 A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension.J Biol Chem. 2013 Sep 6;288(36):25701-25716. doi: 10.1074/jbc.M113.502674. Epub 2013 Jul 26.
20 Refined mapping of the human Ets-related gene Elk-1 to Xp11.2-p11.4, distal to the OATL1 region.Hum Genet. 1994 Oct;94(4):442-4. doi: 10.1007/BF00201610.
21 Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.PLoS Genet. 2013;9(10):e1003870. doi: 10.1371/journal.pgen.1003870. Epub 2013 Oct 10.
22 MZF-1/Elk-1 interaction domain as therapeutic target for protein kinase C-based triple-negative breast cancer cells.Oncotarget. 2016 Sep 13;7(37):59845-59859. doi: 10.18632/oncotarget.11337.
23 Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells.Int J Biochem Cell Biol. 2012 Feb;44(2):302-10. doi: 10.1016/j.biocel.2011.10.025. Epub 2011 Nov 7.
24 Antisense oligonucleotide Elk-1 suppresses the tumorigenicity of human hepatocellular carcinoma cells.Cell Biol Int. 2008 Feb;32(2):210-6. doi: 10.1016/j.cellbi.2007.08.027. Epub 2007 Sep 7.
25 Advances in antibody therapeutics targeting small-cell lung cancer.Adv Clin Exp Med. 2018 Sep;27(9):1317-1323. doi: 10.17219/acem/70159.
26 Expression of protein kinase C and the MZF-1 and elk-1 transcription factors in human bladder transitional cell carcinoma cells.Chin J Physiol. 2012 Apr 30;55(2):75-81. doi: 10.4077/CJP.2012.AMM121.
27 Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation.J Biol Chem. 2007 Mar 2;282(9):6415-24. doi: 10.1074/jbc.M608952200. Epub 2007 Jan 5.
28 A neurotoxic phosphoform of Elk-1 associates with inclusions from multiple neurodegenerative diseases.PLoS One. 2010 Feb 2;5(2):e9002. doi: 10.1371/journal.pone.0009002.
29 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.
30 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
31 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
32 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.