Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4F4UGS)

• DOT Name: Krueppel-like factor 10 (KLF10)
• Synonyms: EGR-alpha; Transforming growth factor-beta-inducible early growth response protein 1; TGFB-inducible early growth response protein 1; TIEG-1
• Gene Name: KLF10
• Related Disease:
  Beta-thalassemia major
  Advanced cancer
  Allergic asthma
  Alpha-1 antitrypsin deficiency
  Beta thalassemia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Endometriosis
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Keloid
  Leukemia
  Liver cirrhosis
  Lung adenocarcinoma
  Myopathy
  Non-insulin dependent diabetes
  Osteoporosis
  Pancreatic adenocarcinoma
  Plasma cell myeloma
  Pneumonia
  Pneumonitis
  Pulmonary disease
  Pulmonary emphysema
  Coronary atherosclerosis
  Myocardial ischemia
  Adenocarcinoma
  Beta-thalassemia intermedia
  Hyperglycemia
  Hypertrophic cardiomyopathy
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Neoplasm
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Pituitary tumor
  Sickle-cell anaemia
  Type-1/2 diabetes
• UniProt ID: KLF10_HUMAN
• PDB ID: 2EPA
• Pfam ID: PF00096
• Sequence:
  MLNFGASLQQTAEERMEMISERPKESMYSWNKTAEKSDFEAVEALMSMSCSWKSDFKKYV
  ENRPVTPVSDLSEEENLLPGTPDFHTIPAFCLTPPYSPSDFEPSQVSNLMAPAPSTVHFK
  SLSDTAKPHIAAPFKEEEKSPVSAPKLPKAQATSVIRHTADAQLCNHQTCPMKAASILNY
  QNNSFRRRTHLNVEAARKNIPCAAVSPNRSKCERNTVADVDEKASAALYDFSVPSSETVI
  CRSQPAPVSPQQKSVLVSPPAVSAGGVPPMPVICQMVPLPANNPVVTTVVPSTPPSQPPA
  VCPPVVFMGTQVPKGAVMFVVPQPVVQSSKPPVVSPNGTRLSPIAPAPGFSPSAAKVTPQ
  IDSSRIRSHICSHPGCGKTYFKSSHLKAHTRTHTGEKPFSCSWKGCERRFARSDELSRHR
  RTHTGEKKFACPMCDRRFMRSDHLTKHARRHLSAKKLPNWQMEVSKLNDIALPPTPAPTQ
• Function: Transcriptional repressor which binds to the consensus sequence 5'-GGTGTG-3'. Plays a role in the regulation of the circadian clock; binds to the GC box sequence in the promoter of the core clock component ARTNL/BMAL1 and represses its transcriptional activity. Regulates the circadian expression of genes involved in lipogenesis, gluconeogenesis, and glycolysis in the liver. Represses the expression of PCK2, a rate-limiting step enzyme of gluconeogenesis. May play a role in the cell cycle regulation.

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beta-thalassemia major	DISW06BV	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Allergic asthma	DISHF0H3	Strong	Biomarker	[3]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Altered Expression	[4]
Beta thalassemia	DIS5RCQK	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[9]
Endometriosis	DISX1AG8	Strong	Biomarker	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Keloid	DISV09JY	Strong	Biomarker	[13]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[4]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[15]
Myopathy	DISOWG27	Strong	Altered Expression	[16]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[17]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[18]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[19]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[20]
Pneumonia	DIS8EF3M	Strong	Biomarker	[3]
Pneumonitis	DIS88E0K	Strong	Biomarker	[3]
Pulmonary disease	DIS6060I	Strong	Biomarker	[3]
Pulmonary emphysema	DIS5M7HZ	Strong	Altered Expression	[4]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[14]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[14]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[21]
Beta-thalassemia intermedia	DISYQ0NL	Limited	Genetic Variation	[1]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[22]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Autosomal dominant	[23]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[24]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[24]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]
Pancreatic cancer	DISJC981	Limited	Biomarker	[2]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[24]
Pituitary tumor	DISN67JD	Limited	Altered Expression	[25]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[1]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Permethrin	DMZ0Q1G	Approved	Krueppel-like factor 10 (KLF10) affects the response to substance of Permethrin.	[50]

24 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 10 (KLF10).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Krueppel-like factor 10 (KLF10).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Krueppel-like factor 10 (KLF10).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Krueppel-like factor 10 (KLF10).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Krueppel-like factor 10 (KLF10).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Krueppel-like factor 10 (KLF10).	[31]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Krueppel-like factor 10 (KLF10).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Krueppel-like factor 10 (KLF10).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Krueppel-like factor 10 (KLF10).	[34]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Krueppel-like factor 10 (KLF10).	[35]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Krueppel-like factor 10 (KLF10).	[36]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Krueppel-like factor 10 (KLF10).	[37]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Krueppel-like factor 10 (KLF10).	[38]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Krueppel-like factor 10 (KLF10).	[39]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Krueppel-like factor 10 (KLF10).	[40]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Krueppel-like factor 10 (KLF10).	[28]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Krueppel-like factor 10 (KLF10).	[41]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Krueppel-like factor 10 (KLF10).	[42]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Krueppel-like factor 10 (KLF10).	[43]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Krueppel-like factor 10 (KLF10).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Krueppel-like factor 10 (KLF10).	[47]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Krueppel-like factor 10 (KLF10).	[48]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Krueppel-like factor 10 (KLF10).	[49]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Krueppel-like factor 10 (KLF10).	[43]

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 Krueppel-like factor 10 (KLF10).	[44]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Krueppel-like factor 10 (KLF10).	[46]

References

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• [3] Klf10 deficiency in mice exacerbates pulmonary inflammation by increasing expression of the proinflammatory molecule NPRA.Int J Biochem Cell Biol. 2016 Oct;79:231-238. doi: 10.1016/j.biocel.2016.08.027. Epub 2016 Aug 31.
• [4] Krppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency.Orphanet J Rare Dis. 2012 May 23;7:29. doi: 10.1186/1750-1172-7-29.
• [5] KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in -hemoglobinopathy patients.Pharmacogenomics. 2012 Oct;13(13):1487-500. doi: 10.2217/pgs.12.125.
• [6] TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway.Mol Cell Biol. 2012 Jan;32(1):50-63. doi: 10.1128/MCB.06152-11. Epub 2011 Oct 24.
• [7] Differential gene expression of TGF beta inducible early gene (TIEG), Smad7, Smad2 and Bard1 in normal and malignant breast tissue.Breast Cancer Res Treat. 2004 Jul;86(1):75-88. doi: 10.1023/B:BREA.0000032926.74216.7d.
• [8] Krppel-Like Factor 10 participates in cervical cancer immunoediting through transcriptional regulation of Pregnancy-Specific Beta-1 Glycoproteins.Sci Rep. 2018 Jun 21;8(1):9445. doi: 10.1038/s41598-018-27711-8.
• [9] Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors.Biochem Biophys Res Commun. 2008 Jun 13;370(4):536-40. doi: 10.1016/j.bbrc.2008.03.066. Epub 2008 Mar 24.
• [10] 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.
• [11] 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.
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• [15] Krppel-like Transcription Factor KLF10 Suppresses TGF-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism.Cancer Res. 2017 May 1;77(9):2387-2400. doi: 10.1158/0008-5472.CAN-16-2589. Epub 2017 Mar 1.
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• [18] TIEG and estrogen modulate SOST expression in the murine skeleton.J Cell Physiol. 2018 Apr;233(4):3540-3551. doi: 10.1002/jcp.26211. Epub 2017 Nov 24.
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• [23] 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.
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• [32] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [33] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [34] 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.
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• [46] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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.
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• [49] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
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