Details of Drug Off-Target (DOT)

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

DOT Name Krueppel-like factor 15 (KLF15)
Synonyms Kidney-enriched krueppel-like factor
Gene Name KLF15
Related Disease
Non-insulin dependent diabetes ( )
Renal fibrosis ( )
Advanced cancer ( )
Aortic aneurysm ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Breast cancer ( )
Breast carcinoma ( )
Congestive heart failure ( )
Coronary heart disease ( )
Duchenne muscular dystrophy ( )
Esophageal squamous cell carcinoma ( )
Fatty liver disease ( )
Hepatitis B virus infection ( )
Hyperglycemia ( )
Metabolic disorder ( )
Myopathy ( )
Neoplasm ( )
Neuralgia ( )
Promyelocytic leukaemia ( )
Prostate cancer ( )
Prostate neoplasm ( )
Retinitis pigmentosa ( )
Vascular disease ( )
Wilms tumor ( )
Colorectal carcinoma ( )
Diabetic kidney disease ( )
Gastric cancer ( )
High blood pressure ( )
Lung adenocarcinoma ( )
Myocardial ischemia ( )
Nephropathy ( )
Osteoarthritis ( )
Stomach cancer ( )
Alopecia ( )
Androgenetic alopecia ( )
Baldness, male pattern ( )
Cardiac failure ( )
Cardiovascular disease ( )
Chronic kidney disease ( )
Chronic obstructive pulmonary disease ( )
Chronic renal failure ( )
Coronary atherosclerosis ( )
End-stage renal disease ( )
Obesity ( )
UniProt ID
KLF15_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
2ENT
Pfam ID
PF00096
Sequence
MVDHLLPVDENFSSPKCPVGYLGDRLVGRRAYHMLPSPVSEDDSDASSPCSCSSPDSQAL
CSCYGGGLGTESQDSILDFLLSQATLGSGGGSGSSIGASSGPVAWGPWRRAAAPVKGEHF
CLPEFPLGDPDDVPRPFQPTLEEIEEFLEENMEPGVKEVPEGNSKDLDACSQLSAGPHKS
HLHPGSSGRERCSPPPGGASAGGAQGPGGGPTPDGPIPVLLQIQPVPVKQESGTGPASPG
QAPENVKVAQLLVNIQGQTFALVPQVVPSSNLNLPSKFVRIAPVPIAAKPVGSGPLGPGP
AGLLMGQKFPKNPAAELIKMHKCTFPGCSKMYTKSSHLKAHLRRHTGEKPFACTWPGCGW
RFSRSDELSRHRRSHSGVKPYQCPVCEKKFARSDHLSKHIKVHRFPRSSRSVRSVN
Function
Transcriptional regulator that binds to the GA element of the CLCNKA promoter. Binds to the KCNIP2 promoter and regulates KCNIP2 circadian expression in the heart. Is a repressor of CCN2 expression, involved in the control of cardiac fibrosis. It is also involved in the control of cardiac hypertrophy acting through the inhibition of MEF2A and GATA4. Involved in podocyte differentiation. Inhibits MYOCD activity. Is a negative regulator of TP53 acetylation. Inhibits NF-kappa-B activation through repression of EP300-dependent RELA acetylation.
Tissue Specificity
Highly expressed in liver, skeletal muscle, and kidney. Expressed in cardiomyocytes. Expression is highly reduced in cardiac tissue of patients with non-ischemic cardiomyopathy and aortic aneurysm, and in glomerular disease. Not expressed in bone marrow or lymphoid tissues.
Reactome Pathway
BMAL1 (R-HSA-1368108 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Non-insulin dependent diabetes DISK1O5Z Definitive Biomarker [1]
Renal fibrosis DISMHI3I Definitive Biomarker [2]
Advanced cancer DISAT1Z9 Strong Biomarker [3]
Aortic aneurysm DISQ5KRA Strong Genetic Variation [4]
Arteriosclerosis DISK5QGC Strong Biomarker [5]
Atherosclerosis DISMN9J3 Strong Biomarker [5]
Breast cancer DIS7DPX1 Strong Altered Expression [6]
Breast carcinoma DIS2UE88 Strong Altered Expression [6]
Congestive heart failure DIS32MEA Strong Biomarker [7]
Coronary heart disease DIS5OIP1 Strong Altered Expression [8]
Duchenne muscular dystrophy DISRQ3NV Strong Altered Expression [9]
Esophageal squamous cell carcinoma DIS5N2GV Strong Biomarker [10]
Fatty liver disease DIS485QZ Strong Biomarker [11]
Hepatitis B virus infection DISLQ2XY Strong Altered Expression [12]
Hyperglycemia DIS0BZB5 Strong Biomarker [13]
Metabolic disorder DIS71G5H Strong Biomarker [14]
Myopathy DISOWG27 Strong Biomarker [9]
Neoplasm DISZKGEW Strong Altered Expression [15]
Neuralgia DISWO58J Strong Biomarker [16]
Promyelocytic leukaemia DISYGG13 Strong Biomarker [17]
Prostate cancer DISF190Y Strong Biomarker [18]
Prostate neoplasm DISHDKGQ Strong Biomarker [18]
Retinitis pigmentosa DISCGPY8 Strong Genetic Variation [19]
Vascular disease DISVS67S Strong Biomarker [5]
Wilms tumor DISB6T16 Strong Altered Expression [20]
Colorectal carcinoma DIS5PYL0 moderate Biomarker [21]
Diabetic kidney disease DISJMWEY moderate Biomarker [22]
Gastric cancer DISXGOUK moderate Altered Expression [23]
High blood pressure DISY2OHH moderate Altered Expression [24]
Lung adenocarcinoma DISD51WR moderate Biomarker [25]
Myocardial ischemia DISFTVXF moderate Biomarker [26]
Nephropathy DISXWP4P moderate Biomarker [27]
Osteoarthritis DIS05URM moderate Altered Expression [28]
Stomach cancer DISKIJSX moderate Altered Expression [23]
Alopecia DIS37HU4 Limited Genetic Variation [29]
Androgenetic alopecia DISSJR1P Limited Genetic Variation [30]
Baldness, male pattern DIS9C9RO Limited Genetic Variation [30]
Cardiac failure DISDC067 Limited Biomarker [7]
Cardiovascular disease DIS2IQDX Limited Biomarker [7]
Chronic kidney disease DISW82R7 Limited Biomarker [27]
Chronic obstructive pulmonary disease DISQCIRF Limited Biomarker [31]
Chronic renal failure DISGG7K6 Limited Altered Expression [32]
Coronary atherosclerosis DISKNDYU Limited Altered Expression [8]
End-stage renal disease DISXA7GG Limited Altered Expression [32]
Obesity DIS47Y1K Limited Biomarker [33]
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⏷ Show the Full List of 45 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
16 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Krueppel-like factor 15 (KLF15). [34]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Krueppel-like factor 15 (KLF15). [35]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Krueppel-like factor 15 (KLF15). [36]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Krueppel-like factor 15 (KLF15). [37]
Triclosan DMZUR4N Approved Triclosan decreases the expression of Krueppel-like factor 15 (KLF15). [38]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Krueppel-like factor 15 (KLF15). [39]
Panobinostat DM58WKG Approved Panobinostat increases the expression of Krueppel-like factor 15 (KLF15). [40]
Niclosamide DMJAGXQ Approved Niclosamide increases the expression of Krueppel-like factor 15 (KLF15). [41]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of Krueppel-like factor 15 (KLF15). [42]
Dihydrotestosterone DM3S8XC Phase 4 Dihydrotestosterone increases the expression of Krueppel-like factor 15 (KLF15). [43]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Krueppel-like factor 15 (KLF15). [40]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone increases the expression of Krueppel-like factor 15 (KLF15). [44]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Krueppel-like factor 15 (KLF15). [46]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Krueppel-like factor 15 (KLF15). [47]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Krueppel-like factor 15 (KLF15). [49]
Tributylstannanyl DMHN7CB Investigative Tributylstannanyl decreases the expression of Krueppel-like factor 15 (KLF15). [50]
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⏷ Show the Full List of 16 Drug(s)
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 Krueppel-like factor 15 (KLF15). [45]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Krueppel-like factor 15 (KLF15). [48]
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References

1 Genetic Variation in Kruppel like Factor 15 Is Associated with Left Ventricular Hypertrophy in Patients with Type 2 Diabetes: Discovery and Replication Cohorts.EBioMedicine. 2017 Apr;18:171-178. doi: 10.1016/j.ebiom.2017.03.036. Epub 2017 Mar 30.
2 Krppel-like factors (KLFs) in renal physiology and disease.EBioMedicine. 2019 Feb;40:743-750. doi: 10.1016/j.ebiom.2019.01.021. Epub 2019 Jan 17.
3 KLF15 promotes the proliferation and metastasis of lung adenocarcinoma cells and has potential as a cancer prognostic marker.Oncotarget. 2017 Oct 19;8(66):109952-109961. doi: 10.18632/oncotarget.21972. eCollection 2017 Dec 15.
4 Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation.Sci Transl Med. 2010 Apr 7;2(26):26ra26. doi: 10.1126/scitranslmed.3000502.
5 Kruppel-like factor 15 is critical for vascular inflammation.J Clin Invest. 2013 Oct;123(10):4232-41. doi: 10.1172/JCI68552. Epub 2013 Sep 3.
6 KLF15 in breast cancer: a novel tumor suppressor?.Cell Oncol (Dordr). 2015 Jun;38(3):227-35. doi: 10.1007/s13402-015-0226-8. Epub 2015 Apr 14.
7 Multiple roles of KLF15 in the heart: Underlying mechanisms and therapeutic implications.J Mol Cell Cardiol. 2019 Apr;129:193-196. doi: 10.1016/j.yjmcc.2019.01.024. Epub 2019 Mar 2.
8 Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure.Lab Invest. 2019 Mar;99(3):371-386. doi: 10.1038/s41374-018-0104-x. Epub 2018 Aug 8.
9 Krppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity.Pharmacol Res. 2018 Apr;130:123-126. doi: 10.1016/j.phrs.2017.12.018. Epub 2017 Dec 27.
10 Cell Signaling Pathway in 12-O-Tetradecanoylphorbol-13-acetate-Induced LCN2 Gene Transcription in Esophageal Squamous Cell Carcinoma.Biomed Res Int. 2017;2017:9592501. doi: 10.1155/2017/9592501. Epub 2017 Oct 2.
11 KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance.PLoS One. 2013 Oct 22;8(10):e77851. doi: 10.1371/journal.pone.0077851. eCollection 2013.
12 Krppel-like factor 15 activates hepatitis B virus gene expression and replication.Hepatology. 2011 Jul;54(1):109-21. doi: 10.1002/hep.24362.
13 Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.JCI Insight. 2019 Feb 21;4(4):e124952. doi: 10.1172/jci.insight.124952. eCollection 2019 Feb 21.
14 Interventions Targeting Glucocorticoid-Krppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.EBioMedicine. 2018 May;31:226-242. doi: 10.1016/j.ebiom.2018.04.024. Epub 2018 May 4.
15 miR-4262 Promotes Proliferation and Invasion of Human Breast Cancer Cells Through Directly Targeting KLF6 and KLF15.Oncol Res. 2017 Jan 26;25(2):277-283. doi: 10.3727/096504016X14732514133203. Epub 2016 Sep 13.
16 KLF15 regulates dopamine D2 receptor and participates in mouse models of neuropathic pain.Biochem Biophys Res Commun. 2017 Oct 14;492(2):269-274. doi: 10.1016/j.bbrc.2017.08.066. Epub 2017 Aug 19.
17 Two Pioneer Transcription Factors, Krppel-Like Transcription Factor 4 and Glucocorticoid Receptor, Cooperatively Transactivate the Bovine Herpesvirus 1 ICP0 Early Promoter and Stimulate Productive Infection.J Virol. 2020 Jan 31;94(4):e01670-19. doi: 10.1128/JVI.01670-19. Print 2020 Jan 31.
18 Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
19 Targeting and silencing of rhodopsin by ectopic expression of the transcription factor KLF15.JCI Insight. 2017 Dec 21;2(24):e96560. doi: 10.1172/jci.insight.96560.
20 Podocyte-Specific Induction of Krppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease.J Am Soc Nephrol. 2018 Oct;29(10):2529-2545. doi: 10.1681/ASN.2018030324. Epub 2018 Aug 24.
21 LncRNA TTN-AS1 sponges miR-376a-3p to promote colorectal cancer progression via upregulating KLF15.Life Sci. 2020 Mar 1;244:116936. doi: 10.1016/j.lfs.2019.116936. Epub 2019 Oct 11.
22 Identification of potential therapeutic target genes in mouse mesangial cells associated with diabetic nephropathy using bioinformatics analysis.Exp Ther Med. 2019 Jun;17(6):4617-4627. doi: 10.3892/etm.2019.7524. Epub 2019 Apr 23.
23 KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression.Dig Dis Sci. 2017 Jun;62(6):1518-1526. doi: 10.1007/s10620-017-4558-2. Epub 2017 Apr 18.
24 Krppel-like factor 15 is a key suppressor of podocyte fibrosis under rotational force-driven pressure.Exp Cell Res. 2020 Jan 1;386(1):111706. doi: 10.1016/j.yexcr.2019.111706. Epub 2019 Nov 4.
25 KLF15 suppresses cell growth and predicts prognosis in lung adenocarcinoma.Biomed Pharmacother. 2018 Oct;106:672-677. doi: 10.1016/j.biopha.2018.07.006. Epub 2018 Jul 11.
26 KLF15-Wnt-Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart.J Am Coll Cardiol. 2019 Oct 8;74(14):1804-1819. doi: 10.1016/j.jacc.2019.07.076.
27 Krppel-like Factor 15: A Potential Therapeutic Target For Kidney Disease.Int J Biol Sci. 2019 Jul 21;15(9):1955-1961. doi: 10.7150/ijbs.34838. eCollection 2019.
28 KLF15 Regulates the Expression of MMP-3 in Human Chondrocytes.J Interferon Cytokine Res. 2018 Aug;38(8):356-362. doi: 10.1089/jir.2017.0135. Epub 2018 Jul 23.
29 Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
30 GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk.Nat Commun. 2017 Nov 17;8(1):1584. doi: 10.1038/s41467-017-01490-8.
31 miR-190a-5p participates in the regulation of hypoxia-induced pulmonary hypertension by targeting KLF15 and can serve as a biomarker of diagnosis and prognosis in chronic obstructive pulmonary disease complicated with pulmonary hypertension.Int J Chron Obstruct Pulmon Dis. 2018 Nov 20;13:3777-3790. doi: 10.2147/COPD.S182504. eCollection 2018.
32 Loss of KLF15 accelerates chronic podocyte injury.Int J Mol Med. 2018 Sep;42(3):1593-1602. doi: 10.3892/ijmm.2018.3726. Epub 2018 Jun 11.
33 Adipose KLF15 Controls Lipid Handling to Adapt to Nutrient Availability.Cell Rep. 2017 Dec 12;21(11):3129-3140. doi: 10.1016/j.celrep.2017.11.032.
34 Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
35 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
36 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
37 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
38 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
39 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.
40 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
41 Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
42 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
43 LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
44 Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
45 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.
46 CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
47 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
48 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.
49 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.
50 Persistent organic pollutants alter DNA methylation during human adipocyte differentiation. Toxicol In Vitro. 2017 Apr;40:79-87. doi: 10.1016/j.tiv.2016.12.011. Epub 2016 Dec 20.