Details of Drug Off-Target (DOT)

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

• DOT Name: Krueppel-like factor 11 (KLF11)
• Synonyms: Transforming growth factor-beta-inducible early growth response protein 2; TGFB-inducible early growth response protein 2; TIEG-2
• Gene Name: KLF11
• Related Disease:
  Stroke
  Advanced cancer
  Alcohol dependence
  Allergic rhinitis
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac disease
  Depression
  Endometriosis
  Gastric cancer
  Hyperglycemia
  Hyperinsulinemia
  Leiomyoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Maturity-onset diabetes of the young type 7
  Metabolic disorder
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Neoplasm
  Pancreatic cancer
  Stomach cancer
  Uterine disorder
  Uterine fibroids
  Neonatal diabetes mellitus
  Maturity-onset diabetes of the young
  Brain infarction
  Hepatocellular carcinoma
  Monogenic diabetes
• UniProt ID: KLF11_HUMAN
• Pfam ID: PF00096
• Sequence:
  MHTPDFAGPDDARAVDIMDICESILERKRHDSERSTCSILEQTDMEAVEALVCMSSWGQR
  SQKGDLLRIRPLTPVSDSGDVTTTVHMDAATPELPKDFHSLSTLCITPPQSPDLVEPSTR
  TPVSPQVTDSKACTATDVLQSSAVVARALSGGAERGLLGLEPVPSSPCRAKGTSVIRHTG
  ESPAACFPTIQTPDCRLSDSREGEEQLLGHFETLQDTHLTDSLLSTNLVSCQPCLHKSGG
  LLLTDKGQQAGWPGAVQTCSPKNYENDLPRKTTPLISVSVPAPPVLCQMIPVTGQSSMLP
  AFLKPPPQLSVGTVRPILAQAAPAPQPVFVGPAVPQGAVMLVLPQGALPPPAPCAANVMA
  AGNTKLLPLAPAPVFITSSQNCVPQVDFSRRRNYVCSFPGCRKTYFKSSHLKAHLRTHTG
  EKPFNCSWDGCDKKFARSDELSRHRRTHTGEKKFVCPVCDRRFMRSDHLTKHARRHMTTK
  KIPGWQAEVGKLNRIASAESPGSPLVSMPASA
• Function: Transcription factor. Activates the epsilon- and gamma-globin gene promoters and, to a much lower degree, the beta-globin gene and represses promoters containing SP1-like binding inhibiting cell growth. Represses transcription of SMAD7 which enhances TGF-beta signaling. Induces apoptosis.
• Tissue Specificity: Ubiquitous. Higher expression in erythroid cells.

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Stroke	DISX6UHX	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[3]
Allergic rhinitis	DIS3U9HN	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Cardiac disease	DISVO1I5	Strong	Biomarker	[7]
Depression	DIS3XJ69	Strong	Biomarker	[8]
Endometriosis	DISX1AG8	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[10]
Hyperinsulinemia	DISIDWT6	Strong	Genetic Variation	[11]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[12]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[13]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[13]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[8]
Maturity-onset diabetes of the young type 7	DISXFS4M	Strong	Autosomal dominant	[14]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[15]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[16]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Pancreatic cancer	DISJC981	Strong	Biomarker	[19]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Uterine disorder	DISGV2SE	Strong	Altered Expression	[20]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[12]
Neonatal diabetes mellitus	DISFHF9K	moderate	Genetic Variation	[21]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[22]
Brain infarction	DISPPGYK	Limited	Biomarker	[23]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[24]
Monogenic diabetes	DISEB8Q0	Refuted	Autosomal dominant	[25]

1 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 Krueppel-like factor 11 (KLF11).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Krueppel-like factor 11 (KLF11).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Krueppel-like factor 11 (KLF11).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Krueppel-like factor 11 (KLF11).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Krueppel-like factor 11 (KLF11).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Krueppel-like factor 11 (KLF11).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Krueppel-like factor 11 (KLF11).	[32]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Krueppel-like factor 11 (KLF11).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Krueppel-like factor 11 (KLF11).	[34]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Krueppel-like factor 11 (KLF11).	[35]
Marinol	DM70IK5	Approved	Marinol increases the expression of Krueppel-like factor 11 (KLF11).	[36]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Krueppel-like factor 11 (KLF11).	[37]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Krueppel-like factor 11 (KLF11).	[38]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Krueppel-like factor 11 (KLF11).	[39]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Krueppel-like factor 11 (KLF11).	[40]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Krueppel-like factor 11 (KLF11).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Krueppel-like factor 11 (KLF11).	[42]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Krueppel-like factor 11 (KLF11).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Krueppel-like factor 11 (KLF11).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Krueppel-like factor 11 (KLF11).	[44]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Krueppel-like factor 11 (KLF11).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Krueppel-like factor 11 (KLF11).	[46]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Krueppel-like factor 11 (KLF11).	[47]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Krueppel-like factor 11 (KLF11).	[48]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid decreases the expression of Krueppel-like factor 11 (KLF11).	[49]

References

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• [2] A novel role of the Sp/KLF transcription factor KLF11 in arresting progression of endometriosis.PLoS One. 2013;8(3):e60165. doi: 10.1371/journal.pone.0060165. Epub 2013 Mar 28.
• [3] A novel role for glyceraldehyde-3-phosphate dehydrogenase and monoamine oxidase B cascade in ethanol-induced cellular damage.Biol Psychiatry. 2010 May 1;67(9):855-63. doi: 10.1016/j.biopsych.2009.10.032. Epub 2009 Dec 22.
• [4] Induction of airway progenitor cells via p63 and KLF11 by Rho-kinase inhibitor Y27632 in hTERT-human nasal epithelial cells.Am J Transl Res. 2019 Feb 15;11(2):599-611. eCollection 2019.
• [5] microRNA-30d mediated breast cancer invasion, migration, and EMT by targeting KLF11 and activating STAT3 pathway.J Cell Biochem. 2018 Nov;119(10):8138-8145. doi: 10.1002/jcb.26767. Epub 2018 Jun 19.
• [6] KLF11 promotes gastric cancer invasion and migration by increasing Twist1 expression.Neoplasma. 2019 Jan 15;66(1):92-100. doi: 10.4149/neo_2018_180325N201. Epub 2018 Sep 4.
• [7] Knockdown of KLF11 attenuates hypoxia/reoxygenation injury via JAK2/STAT3 signaling in H9c2.Apoptosis. 2017 Apr;22(4):510-518. doi: 10.1007/s10495-016-1327-1.
• [8] Evidence revealing deregulation of the KLF11-MAO A pathway in association with chronic stress and depressive disorders.Neuropsychopharmacology. 2015 May;40(6):1373-82. doi: 10.1038/npp.2014.321. Epub 2014 Dec 15.
• [9] KLF11 is an Epigenetic Mediator of DRD2/Dopaminergic Signaling in Endometriosis.Reprod Sci. 2017 Aug;24(8):1129-1138. doi: 10.1177/1933719117698582. Epub 2017 Apr 4.
• [10] Involvement of KLF11 in hepatic glucose metabolism in mice via suppressing of PEPCK-C expression.PLoS One. 2014 Feb 26;9(2):e89552. doi: 10.1371/journal.pone.0089552. eCollection 2014.
• [11] Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes.Endocrinology. 2015 Oct;156(10):3581-95. doi: 10.1210/en.2015-1145. Epub 2015 Aug 6.
• [12] The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development.Reprod Sci. 2016 Feb;23(2):163-75. doi: 10.1177/1933719115584449. Epub 2015 Apr 28.
• [13] Radiotherapy in combination with hyperthermia suppresses lung cancer progression via increased NR4A3 and KLF11 expression.Int J Radiat Biol. 2019 Dec;95(12):1696-1707. doi: 10.1080/09553002.2019.1665213. Epub 2019 Sep 17.
• [14] Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4807-12. doi: 10.1073/pnas.0409177102. Epub 2005 Mar 17.
• [15] Krppel-like factor 11 regulates the expression of metabolic genes via an evolutionarily conserved protein interaction domain functionally disrupted in maturity onset diabetes of the young.J Biol Chem. 2013 Jun 14;288(24):17745-58. doi: 10.1074/jbc.M112.434670. Epub 2013 Apr 15.
• [16] Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis.FASEB J. 2012 Dec;26(12):4937-50. doi: 10.1096/fj.12-209502. Epub 2012 Aug 28.
• [17] Epigenetic inactivation of tumour suppressor gene KLF11 in myelodysplastic syndromes*.Eur J Haematol. 2010 Apr;84(4):298-303. doi: 10.1111/j.1600-0609.2009.01389.x. Epub 2009 Nov 28.
• [18] Sequence-specific recruitment of heterochromatin protein 1 via interaction with Krppel-like factor 11, a human transcription factor involved in tumor suppression and metabolic diseases.J Biol Chem. 2012 Apr 13;287(16):13026-39. doi: 10.1074/jbc.M112.342634. Epub 2012 Feb 8.
• [19] The tumor suppressor KLF11 mediates a novel mechanism in transforming growth factor beta-induced growth inhibition that is inactivated in pancreatic cancer.Mol Cancer Res. 2006 Nov;4(11):861-72. doi: 10.1158/1541-7786.MCR-06-0081.
• [20] KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis.Biol Reprod. 2016 Sep;95(3):62. doi: 10.1095/biolreprod.116.140764. Epub 2016 Aug 3.
• [21] Krppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-B signaling pathway.Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):2981-8. doi: 10.1161/ATVBAHA.112.300349. Epub 2012 Oct 4.
• [22] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [23] Genetic Deletion of Krppel-Like Factor 11 Aggravates Ischemic Brain Injury.Mol Neurobiol. 2018 Apr;55(4):2911-2921. doi: 10.1007/s12035-017-0556-9. Epub 2017 Apr 29.
• [24] MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/KLF11/Smads in hepatocellular carcinoma.Cancer Cell Int. 2018 Jan 17;18:10. doi: 10.1186/s12935-018-0508-0. eCollection 2018.
• [25] 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.
• [26] 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.
• [27] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [28] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [29] 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.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [32] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [33] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [34] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [35] 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.
• [36] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [37] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [38] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [39] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [40] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [41] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [42] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [43] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [44] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [45] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [46] 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.
• [47] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [48] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [49] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.