Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIIAC18)

• DOT Name: Krueppel-like factor 3 (KLF3)
• Synonyms: Basic krueppel-like factor; CACCC-box-binding protein BKLF; TEF-2
• Gene Name: KLF3
• Related Disease:
  Advanced cancer
  Aortic valve stenosis
  Cardiovascular disease
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Malignant soft tissue neoplasm
  Melanoma
  Neoplasm
  Sarcoma
• UniProt ID: KLF3_HUMAN
• Pfam ID: PF00096
• Sequence:
  MLMFDPVPVKQEAMDPVSVSYPSNYMESMKPNKYGVIYSTPLPEKFFQTPEGLSHGIQME
  PVDLTVNKRSSPPSAGNSPSSLKFPSSHRRASPGLSMPSSSPPIKKYSPPSPGVQPFGVP
  LSMPPVMAAALSRHGIRSPGILPVIQPVVVQPVPFMYTSHLQQPLMVSLSEEMENSSSSM
  QVPVIESYEKPISQKKIKIEPGIEPQRTDYYPEEMSPPLMNSVSPPQALLQENHPSVIVQ
  PGKRPLPVESPDTQRKRRIHRCDYDGCNKVYTKSSHLKAHRRTHTGEKPYKCTWEGCTWK
  FARSDELTRHFRKHTGIKPFQCPDCDRSFSRSDHLALHRKRHMLV
• Function: Binds to the CACCC box of erythroid cell-expressed genes. May play a role in hematopoiesis.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Aortic valve stenosis	DISW7AQ9	Strong	Genetic Variation	[2]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Sarcoma	DISZDG3U	Strong	Altered Expression	[5]

3 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 3 (KLF3).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Krueppel-like factor 3 (KLF3).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Krueppel-like factor 3 (KLF3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Krueppel-like factor 3 (KLF3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Krueppel-like factor 3 (KLF3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Krueppel-like factor 3 (KLF3).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Krueppel-like factor 3 (KLF3).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Krueppel-like factor 3 (KLF3).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Krueppel-like factor 3 (KLF3).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Krueppel-like factor 3 (KLF3).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Krueppel-like factor 3 (KLF3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Krueppel-like factor 3 (KLF3).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Krueppel-like factor 3 (KLF3).	[18]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Krueppel-like factor 3 (KLF3).	[19]

References

• [1] NEAT1/miR-23a-3p/KLF3: a novel regulatory axis in melanoma cancer progression.Cancer Cell Int. 2019 Aug 22;19:217. doi: 10.1186/s12935-019-0927-6. eCollection 2019.
• [2] ENU-induced mutation in the DNA-binding domain of KLF3 reveals important roles for KLF3 in cardiovascular development and function in mice.PLoS Genet. 2013;9(7):e1003612. doi: 10.1371/journal.pgen.1003612. Epub 2013 Jul 11.
• [3] RNA sequencing analysis reveals protective role of kruppel-like factor 3 in colorectal cancer.Oncotarget. 2017 Mar 28;8(13):21984-21993. doi: 10.18632/oncotarget.15766.
• [4] MiR-326/Sp1/KLF3: A novel regulatory axis in lung cancer progression.Cell Prolif. 2019 Mar;52(2):e12551. doi: 10.1111/cpr.12551. Epub 2018 Nov 28.
• [5] Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182.Cancer Lett. 2015 Dec 1;369(1):202-11. doi: 10.1016/j.canlet.2015.08.016. Epub 2015 Aug 24.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [9] 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.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.