Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVH4KD4)

• DOT Name: Krueppel-like factor 12 (KLF12)
• Synonyms: Transcriptional repressor AP-2rep
• Gene Name: KLF12
• Related Disease:
  Advanced cancer
  Autism spectrum disorder
  Cryohydrocytosis
  Cytomegalovirus infection
  Drug dependence
  Endometrial cancer
  Endometrial carcinoma
  Esophageal adenocarcinoma
  Intellectual disability
  Narcolepsy
  Neoplasm
  Pervasive developmental disorder
  Prostate cancer
  Prostate carcinoma
  Substance abuse
  Substance dependence
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Gastric cancer
  Major depressive disorder
  Pancreatic cancer
  Stomach cancer
  Autosomal dominant polycystic kidney disease
  Type-1/2 diabetes
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Neuroendocrine neoplasm
  Schizophrenia
• UniProt ID: KLF12_HUMAN
• Pfam ID: PF00096
• Sequence:
  MNIHMKRKTIKNINTFENRMLMLDGMPAVRVKTELLESEQGSPNVHNYPDMEAVPLLLNN
  VKGEPPEDSLSVDHFQTQTEPVDLSINKARTSPTAVSSSPVSMTASASSPSSTSTSSSSS
  SRLASSPTVITSVSSASSSSTVLTPGPLVASASGVGGQQFLHIIHPVPPSSPMNLQSNKL
  SHVHRIPVVVQSVPVVYTAVRSPGNVNNTIVVPLLEDGRGHGKAQMDPRGLSPRQSKSDS
  DDDDLPNVTLDSVNETGSTALSIARAVQEVHPSPVSRVRGNRMNNQKFPCSISPFSIEST
  RRQRRSESPDSRKRRIHRCDFEGCNKVYTKSSHLKAHRRTHTGEKPYKCTWEGCTWKFAR
  SDELTRHYRKHTGVKPFKCADCDRSFSRSDHLALHRRRHMLV
• Function: Confers strong transcriptional repression to the AP-2-alpha gene. Binds to a regulatory element (A32) in the AP-2-alpha gene promoter.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Cryohydrocytosis	DISMQHL3	Strong	Genetic Variation	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[4]
Drug dependence	DIS9IXRC	Strong	Biomarker	[5]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[6]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[6]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Substance abuse	DIS327VW	Strong	Biomarker	[5]
Substance dependence	DISDRAAR	Strong	Biomarker	[5]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[10]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[10]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[10]
Gastric cancer	DISXGOUK	moderate	Biomarker	[11]
Major depressive disorder	DIS4CL3X	moderate	Genetic Variation	[10]
Pancreatic cancer	DISJC981	moderate	Biomarker	[12]
Stomach cancer	DISKIJSX	moderate	Biomarker	[11]
Autosomal dominant polycystic kidney disease	DISBHWUI	Disputed	Biomarker	[13]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[14]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[15]
Lung cancer	DISCM4YA	Limited	Altered Expression	[16]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[16]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[17]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[18]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Krueppel-like factor 12 (KLF12).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Krueppel-like factor 12 (KLF12).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Krueppel-like factor 12 (KLF12).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Krueppel-like factor 12 (KLF12).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Krueppel-like factor 12 (KLF12).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Krueppel-like factor 12 (KLF12).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Krueppel-like factor 12 (KLF12).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Krueppel-like factor 12 (KLF12).	[28]
Marinol	DM70IK5	Approved	Marinol increases the expression of Krueppel-like factor 12 (KLF12).	[29]
Selenium	DM25CGV	Approved	Selenium increases the expression of Krueppel-like factor 12 (KLF12).	[30]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Krueppel-like factor 12 (KLF12).	[31]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Krueppel-like factor 12 (KLF12).	[32]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Krueppel-like factor 12 (KLF12).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Krueppel-like factor 12 (KLF12).	[28]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Krueppel-like factor 12 (KLF12).	[34]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Krueppel-like factor 12 (KLF12).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Krueppel-like factor 12 (KLF12).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Krueppel-like factor 12 (KLF12).	[38]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Krueppel-like factor 12 (KLF12).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Krueppel-like factor 12 (KLF12).	[35]

References

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• [3] Sustained viral response and treatment-induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin-treated Chinese chronic hepatitis C patients.J Gastroenterol Hepatol. 2016 Aug;31(8):1489-97. doi: 10.1111/jgh.13290.
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• [7] Krppel-Like Factor 12 Promotes Colorectal Cancer Growth through Early Growth Response Protein 1.PLoS One. 2016 Jul 21;11(7):e0159899. doi: 10.1371/journal.pone.0159899. eCollection 2016.
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• [13] Regulation of KLF12 by microRNA-20b and microRNA-106a in cystogenesis.FASEB J. 2018 Jul;32(7):3574-3582. doi: 10.1096/fj.201700923R. Epub 2018 Feb 16.
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• [17] MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis.Mol Cancer. 2017 Jan 17;16(1):11. doi: 10.1186/s12943-017-0582-2.
• [18] Integrative microRNA-mRNA and protein-protein interaction analysis in pancreatic neuroendocrine tumors.Eur Rev Med Pharmacol Sci. 2016 Jul;20(13):2842-52.
• [19] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
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• [22] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [23] 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.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
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• [30] Changes in gene expression profiles in response to selenium supplementation among individuals with arsenic-induced pre-malignant skin lesions. Toxicol Lett. 2007 Mar 8;169(2):162-76. doi: 10.1016/j.toxlet.2007.01.006. Epub 2007 Jan 19.
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• [34] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [35] 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.
• [36] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [37] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [38] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.