Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3I5FLB)

• DOT Name: Potassium voltage-gated channel subfamily H member 8 (KCNH8)
• Synonyms: ELK1; hElk1; Ether-a-go-go-like potassium channel 3; ELK channel 3; ELK3; Voltage-gated potassium channel subunit Kv12.1
• Gene Name: KCNH8
• Related Disease:
  Bladder transitional cell carcinoma
  Congenital thrombotic thrombocytopenic purpura
  Neuroblastoma
  Thrombotic thrombocytopenic purpura
  Vein disorder
  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
  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
  Tarsal-carpal coalition syndrome
  Familial medullary thyroid carcinoma
  Lewy body dementia
• UniProt ID: KCNH8_HUMAN
• Pfam ID: PF00027 ; PF00520 ; PF13426
• Sequence:
  MPVMKGLLAPQNTFLDTIATRFDGTHSNFILANAQVAKGFPIVYCSDGFCELAGFARTEV
  MQKSCSCKFLFGVETNEQLMLQIEKSLEEKTEFKGEIMFYKKNGSPFWCLLDIVPIKNEK
  GDVVLFLASFKDITDTKVKITPEDKKEDKVKGRSRAGTHFDSARRRSRAVLYHISGHLQR
  REKNKLKINNNVFVDKPAFPEYKVSDAKKSKFILLHFSTFKAGWDWLILLATFYVAVTVP
  YNVCFIGNDDLSTTRSTTVSDIAVEILFIIDIILNFRTTYVSKSGQVIFEARSICIHYVT
  TWFIIDLIAALPFDLLYAFNVTVVSLVHLLKTVRLLRLLRLLQKLDRYSQHSTIVLTLLM
  SMFALLAHWMACIWYVIGKMEREDNSLLKWEVGWLHELGKRLESPYYGNNTLGGPSIRSA
  YIAALYFTLSSLTSVGFGNVSANTDAEKIFSICTMLIGALMHALVFGNVTAIIQRMYSRW
  SLYHTRTKDLKDFIRVHHLPQQLKQRMLEYFQTTWSVNNGIDSNELLKDFPDELRSDITM
  HLNKEILQLSLFECASRGCLRSLSLHIKTSFCAPGEYLLRQGDALQAIYFVCSGSMEVLK
  DSMVLAILGKGDLIGANLSIKDQVIKTNADVKALTYCDLQCIILKGLFEVLDLYPEYAHK
  FVEDIQHDLTYNLREGHESDVISRLSNKSMVSQSEPKGNGNINKRLPSIVEDEEEEEEGE
  EEEAVSLSPICTRGSSSRNKKVGSNKAYLGLSLKQLASGTVPFHSPIRVSRSNSPKTKQE
  IDPPNHNKRKEKNLKLQLSTLNNAGPPDLSPRIVDGIEDGNSSEESQTFDFGSERIRSEP
  RISPPLGDPEIGAAVLFIKAEETKQQINKLNSEVTTLTQEVSQLGKDMRNVIQLLENVLS
  PQQPSRFCSLHSTSVCPSRESLQTRTSWSAHQPCLHLQTGGAAYTQAQLCSSNITSDIWS
  VDPSSVGSSPQRTGAHEQNPADSELYHSPSLDYSPSHYQVVQEGHLQFLRCISPHSDSTL
  TPLQSISATLSSSVCSSSETSLHLVLPSRSEEGSFSQGTVSSFSLENLPGSWNQEGMASA
  STKPLENLPLEVVTSTAEVKDNKAINV
• Function: Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a slowly activating, outward rectifying current. Channel properties may be modulated by cAMP and subunit assembly.
• Tissue Specificity: Primarily expressed in the nervous system.
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Congenital thrombotic thrombocytopenic purpura	DISC8GS9	Definitive	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[3]
Thrombotic thrombocytopenic purpura	DIS3LDOU	Definitive	Altered Expression	[2]
Vein disorder	DISJQJNZ	Definitive	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[7]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[7]
Breast adenocarcinoma	DISMPHJ0	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[10]
Depression	DIS3XJ69	Strong	Biomarker	[11]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[12]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Huntington disease	DISQPLA4	Strong	Biomarker	[15]
Insulinoma	DISIU1JS	Strong	Altered Expression	[16]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[17]
Premature aging syndrome	DIS51AGT	Strong	Altered Expression	[18]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Altered Expression	[19]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Altered Expression	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[22]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[22]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[23]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[24]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[25]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[26]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[25]
Liver cancer	DISDE4BI	moderate	Biomarker	[26]
Lung cancer	DISCM4YA	moderate	Altered Expression	[14]
Tarsal-carpal coalition syndrome	DISY90L2	Disputed	Altered Expression	[1]
Familial medullary thyroid carcinoma	DIS01PWX	Limited	Genetic Variation	[27]
Lewy body dementia	DISAE66J	Limited	Biomarker	[28]

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 Potassium voltage-gated channel subfamily H member 8 (KCNH8).	[29]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium voltage-gated channel subfamily H member 8 (KCNH8).	[30]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Potassium voltage-gated channel subfamily H member 8 (KCNH8).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium voltage-gated channel subfamily H member 8 (KCNH8).	[34]

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 increases the methylation of Potassium voltage-gated channel subfamily H member 8 (KCNH8).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Potassium voltage-gated channel subfamily H member 8 (KCNH8).	[33]

References

• [1] 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.
• [2] ApoA-1 Mimetic Peptide ELK-2A2K2E Decreases Inflammatory Factor Levels Through the ABCA1-JAK2-STAT3-TTP Axis in THP-1-Derived Macrophages.J Cardiovasc Pharmacol. 2018 Jul;72(1):60-67. doi: 10.1097/FJC.0000000000000594.
• [3] 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.
• [4] Genome-wide association analysis for chronic venous disease identifies EFEMP1 and KCNH8 as susceptibility loci.Sci Rep. 2017 Apr 4;7:45652. doi: 10.1038/srep45652.
• [5] Genome-wide characterization of lncRNAs in acute myeloid leukemia.Brief Bioinform. 2018 Jul 20;19(4):627-635. doi: 10.1093/bib/bbx007.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [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] 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.
• [30] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [31] 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.
• [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.
• [33] 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.
• [34] 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.