Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMIKHZ4)

• DOT Name: Krueppel-like factor 13 (KLF13)
• Synonyms: Basic transcription element-binding protein 3; BTE-binding protein 3; Novel Sp1-like zinc finger transcription factor 1; RANTES factor of late activated T-lymphocytes 1; RFLAT-1; Transcription factor BTEB3; Transcription factor NSLP1
• Gene Name: KLF13
• Related Disease:
  Acute myocardial infarction
  Advanced cancer
  Cardiac disease
  Cardiac failure
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Endometriosis
  Glioma
  Holt-Oram syndrome
  Inflammatory bowel disease
  Neoplasm
  Obesity
  Systemic lupus erythematosus
  Ventricular septal defect
  Congenital heart disease
  Immune system disorder
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Eosinophilic esophagitis
  Myocardial infarction
  Psoriasis
• UniProt ID: KLF13_HUMAN
• Pfam ID: PF00096
• Sequence:
  MAAAAYVDHFAAECLVSMSSRAVVHGPREGPESRPEGAAVAATPTLPRVEERRDGKDSAS
  LFVVARILADLNQQAPAPAPAERREGAAARKARTPCRLPPPAPEPTSPGAEGAAAAPPSP
  AWSEPEPEAGLEPEREPGPAGSGEPGLRQRVRRGRSRADLESPQRKHKCHYAGCEKVYGK
  SSHLKAHLRTHTGERPFACSWQDCNKKFARSDELARHYRTHTGEKKFSCPICEKRFMRSD
  HLTKHARRHANFHPGMLQRRGGGSRTGSLSDYSRSDASSPTISPASSP
• Function: Represses transcription by binding to the BTE site, a GC-rich DNA element, in competition with the activator SP1. It also represses transcription by interacting with the corepressor Sin3A and HDAC1. Activates RANTES expression in T-cells.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Holt-Oram syndrome	DISBNDZ2	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[12]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[9]
Congenital heart disease	DISQBA23	Moderate	Autosomal dominant	[13]
Immune system disorder	DISAEGPH	moderate	Biomarker	[14]
Prostate cancer	DISF190Y	moderate	Biomarker	[14]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	moderate	Altered Expression	[14]
Eosinophilic esophagitis	DISR8WSB	Limited	Biomarker	[15]
Myocardial infarction	DIS655KI	Limited	Biomarker	[1]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[16]

4 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 13 (KLF13).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Krueppel-like factor 13 (KLF13).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Krueppel-like factor 13 (KLF13).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Krueppel-like factor 13 (KLF13).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Krueppel-like factor 13 (KLF13).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Krueppel-like factor 13 (KLF13).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Krueppel-like factor 13 (KLF13).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Krueppel-like factor 13 (KLF13).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Krueppel-like factor 13 (KLF13).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Krueppel-like factor 13 (KLF13).	[24]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Krueppel-like factor 13 (KLF13).	[27]

References

• [1] A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes.J Mol Cell Cardiol. 2018 Jan;114:72-82. doi: 10.1016/j.yjmcc.2017.11.003. Epub 2017 Nov 7.
• [2] Overexpression of KLF13 and FGFR3 in oral cancer cells.Cytogenet Genome Res. 2010 Jun;128(4):192-8. doi: 10.1159/000308303. Epub 2010 Jun 2.
• [3] The Kruppel-like transcription factor KLF13 is a novel regulator of heart development.EMBO J. 2006 Nov 1;25(21):5201-13. doi: 10.1038/sj.emboj.7601379. Epub 2006 Oct 19.
• [4] MiR-147b inhibits cell viability and promotes apoptosis of rat H9c2 cardiomyocytes via down-regulating KLF13 expression.Acta Biochim Biophys Sin (Shanghai). 2018 Mar 1;50(3):288-297. doi: 10.1093/abbs/gmx144.
• [5] KLF13 regulates the differentiation-dependent human papillomavirus life cycle in keratinocytes through STAT5 and IL-8.Oncogene. 2016 Oct 20;35(42):5565-5575. doi: 10.1038/onc.2016.97. Epub 2016 Apr 4.
• [6] Integrated analysis of gene expression signatures associated with colon cancer from three datasets.Gene. 2018 May 15;654:95-102. doi: 10.1016/j.gene.2018.02.007. Epub 2018 Feb 3.
• [7] Krppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis.Biol Reprod. 2015 Jun;92(6):140. doi: 10.1095/biolreprod.115.130260. Epub 2015 Apr 22.
• [8] Downregulation of KLF13 through DNMT1-mediated hypermethylation promotes glioma cell proliferation and invasion.Onco Targets Ther. 2019 Feb 22;12:1509-1520. doi: 10.2147/OTT.S188270. eCollection 2019.
• [9] KLF13 is a genetic modifier of the Holt-Oram syndrome gene TBX5.Hum Mol Genet. 2017 Mar 1;26(5):942-954. doi: 10.1093/hmg/ddx009.
• [10] MicroRNA-125a suppresses intestinal mucosal inflammation through targeting ETS-1 in patients with inflammatory bowel diseases.J Autoimmun. 2019 Jul;101:109-120. doi: 10.1016/j.jaut.2019.04.014. Epub 2019 Apr 20.
• [11] A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels.Int J Obes (Lond). 2017 Jun;41(6):990-994. doi: 10.1038/ijo.2017.43. Epub 2017 Feb 14.
• [12] Circular RNAS: novel biomarkers of disease activity in systemic lupus erythematosus?.Clin Sci (Lond). 2019 May 7;133(9):1049-1052. doi: 10.1042/CS20180826. Print 2019 May 15.
• [13] 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.
• [14] Transcription factor KLF13 inhibits AKT activation and suppresses the growth of prostate carcinoma cells.Cancer Biomark. 2018;22(3):533-541. doi: 10.3233/CBM-181196.
• [15] Early-life environmental exposures interact with genetic susceptibility variants in pediatric patients with eosinophilic esophagitis.J Allergy Clin Immunol. 2018 Feb;141(2):632-637.e5. doi: 10.1016/j.jaci.2017.07.010. Epub 2017 Oct 10.
• [16] Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.Nat Commun. 2017 May 24;8:15382. doi: 10.1038/ncomms15382.
• [17] 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.
• [18] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [19] 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.
• [20] 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.
• [21] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] 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.
• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.