Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLZGS7J)

• DOT Name: Forkhead box protein K1 (FOXK1)
• Synonyms: Myocyte nuclear factor; MNF
• Gene Name: FOXK1
• Related Disease:
  Adult glioblastoma
  Autism
  B-cell lymphoma
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hypothyroidism
  Knee osteoarthritis
  Lung cancer
  Lung carcinoma
  Neoplasm of esophagus
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Metastatic malignant neoplasm
  Pancreatic cancer
  Advanced cancer
  Epidermodysplasia verruciformis
  Gastric cancer
  Malignant pleural mesothelioma
  Neoplasm
  Stomach cancer
• UniProt ID: FOXK1_HUMAN
• Pfam ID: PF00498 ; PF00250
• Sequence:
  MAEVGEDSGARALLALRSAPCSPVLCAAAAAAAFPAAAPPPAPAQPQPPPGPPPPPPPPL
  PPGAIAGAGSSGGSSGVSGDSAVAGAAPALVAAAAASVRQSPGPALARLEGREFEFLMRQ
  PSVTIGRNSSQGSVDLSMGLSSFISRRHLQLSFQEPHFYLRCLGKNGVFVDGAFQRRGAP
  ALQLPKQCTFRFPSTAIKIQFTSLYHKEEAPASPLRPLYPQISPLKIHIPEPDLRSMVSP
  VPSPTGTISVPNSCPASPRGAGSSSYRFVQNVTSDLQLAAEFAAKAASEQQADTSGGDSP
  KDESKPPFSYAQLIVQAISSAQDRQLTLSGIYAHITKHYPYYRTADKGWQNSIRHNLSLN
  RYFIKVPRSQEEPGKGSFWRIDPASEAKLVEQAFRKRRQRGVSCFRTPFGPLSSRSAPAS
  PTHPGLMSPRSGGLQTPECLSREGSPIPHDPEFGSKLASVPEYRYSQSAPGSPVSAQPVI
  MAVPPRPSSLVAKPVAYMPASIVTSQQPAGHAIHVVQQAPTVTMVRVVTTSANSANGYIL
  TSQGAAGGSHDAAGAAVLDLGSEARGLEEKPTIAFATIPAAGGVIQTVASQMAPGVPGHT
  VTILQPATPVTLGQHHLPVRAVTQNGKHAVPTNSLAGNAYALTSPLQLLATQASSSAPVV
  VTRVCEVGPKEPAAAVAATATTTPATATTASASASSTGEPEVKRSRVEEPSGAVTTPAGV
  IAAAGPQGPGTGE
• Function: Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy. Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context. Together with FOXK2, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen. Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4. Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate. Involved in mTORC1-mediated metabolic reprogramming: in response to mTORC1 signaling, translocates into the nucleus and regulates the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby regulating glucose metabolism. Together with FOXK2, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins. Acts as a transcriptional regulator of the myogenic progenitor cell population in skeletal muscle. Binds to the upstream enhancer region (CCAC box) of myoglobin (MB) gene, regulating the myogenic progenitor cell population. Promotes muscle progenitor cell proliferation by repressing the transcriptional activity of FOXO4, thereby inhibiting myogenic differentiation. Involved in remodeling processes of adult muscles that occur in response to physiological stimuli. Required to correct temporal orchestration of molecular and cellular events necessary for muscle repair. Represses myogenic differentiation by inhibiting MEFC activity. Positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus. Reduces virus replication, probably by binding the interferon stimulated response element (ISRE) to promote antiviral gene expression.
• Tissue Specificity: Expressed both developing and adult tissues . In adults, significant expression is seen in tumors of the brain, colon and lymph node .
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Posttranslational Modification	[2]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[13]
Knee osteoarthritis	DISLSNBJ	Strong	Altered Expression	[14]
Lung cancer	DISCM4YA	Strong	Altered Expression	[15]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[15]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[6]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[12]
Liver cancer	DISDE4BI	moderate	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[17]
Pancreatic cancer	DISJC981	moderate	Biomarker	[18]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[19]
Epidermodysplasia verruciformis	DIS54WBS	Limited	Biomarker	[20]
Gastric cancer	DISXGOUK	Limited	Biomarker	[21]
Malignant pleural mesothelioma	DIST2R60	Limited	Genetic Variation	[22]
Neoplasm	DISZKGEW	Limited	Biomarker	[19]
Stomach cancer	DISKIJSX	Limited	Biomarker	[21]

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 Forkhead box protein K1 (FOXK1).	[23]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Forkhead box protein K1 (FOXK1).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Forkhead box protein K1 (FOXK1).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Forkhead box protein K1 (FOXK1).	[33]

9 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 Forkhead box protein K1 (FOXK1).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Forkhead box protein K1 (FOXK1).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Forkhead box protein K1 (FOXK1).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Forkhead box protein K1 (FOXK1).	[27]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Forkhead box protein K1 (FOXK1).	[29]
Marinol	DM70IK5	Approved	Marinol increases the expression of Forkhead box protein K1 (FOXK1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Forkhead box protein K1 (FOXK1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Forkhead box protein K1 (FOXK1).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Forkhead box protein K1 (FOXK1).	[34]

References

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• [3] Identification of potential key genes associated with diffuse large B-cell lymphoma based on microarray gene expression profiling.Neoplasma. 2017;64(6):824-833. doi: 10.4149/neo_2017_603.
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• [7] Knockdown of FOXK1 alone or in combination with apoptosis-inducing 5-FU inhibits cell growth in colorectal cancer.Oncol Rep. 2016 Oct;36(4):2151-9. doi: 10.3892/or.2016.5041. Epub 2016 Aug 25.
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• [10] MicroRNA-652 suppresses malignant phenotypes in glioblastoma multiforme via FOXK1-mediated AKT/mTOR signaling pathway.Onco Targets Ther. 2019 Jul 10;12:5563-5575. doi: 10.2147/OTT.S204715. eCollection 2019.
• [11] ZRANB2/SNHG20/FOXK1 Axis regulates Vasculogenic mimicry formation in glioma.J Exp Clin Cancer Res. 2019 Feb 11;38(1):68. doi: 10.1186/s13046-019-1073-7.
• [12] High FOXK1 expression correlates with poor outcomes in hepatocellular carcinoma and regulates stemness of hepatocellular carcinoma cells.Life Sci. 2019 Jul 1;228:128-134. doi: 10.1016/j.lfs.2019.04.068. Epub 2019 May 1.
• [13] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [14] Neuromuscular function of the quadriceps muscle during isometric maximal, submaximal and submaximal fatiguing voluntary contractions in knee osteoarthrosis patients.PLoS One. 2017 May 15;12(5):e0176976. doi: 10.1371/journal.pone.0176976. eCollection 2017.
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• [17] Oncogene FOXK1 enhances invasion of colorectal carcinoma by inducing epithelial-mesenchymal transition.Oncotarget. 2016 Aug 9;7(32):51150-51162. doi: 10.18632/oncotarget.9457.
• [18] Long non-coding RNA MCM3AP-AS1 promotes growth and migration through modulating FOXK1 by sponging miR-138-5p in pancreatic cancer.Mol Med. 2019 Dec 12;25(1):55. doi: 10.1186/s10020-019-0121-2.
• [19] IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner.Nucleic Acids Res. 2019 Jan 10;47(1):375-390. doi: 10.1093/nar/gky1012.
• [20] Adenovirus type 5 E1A and E6 proteins of low-risk cutaneous beta-human papillomaviruses suppress cell transformation through interaction with FOXK1/K2 transcription factors.J Virol. 2010 Mar;84(6):2719-31. doi: 10.1128/JVI.02119-09. Epub 2010 Jan 6.
• [21] Coexpression of FOXK1 and vimentin promotes EMT, migration, and invasion in gastric cancer cells.J Mol Med (Berl). 2019 Feb;97(2):163-176. doi: 10.1007/s00109-018-1720-z. Epub 2018 Nov 27.
• [22] Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects.J Thorac Oncol. 2019 Mar;14(3):527-539. doi: 10.1016/j.jtho.2018.10.163. Epub 2018 Nov 5.
• [23] 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.
• [24] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [25] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [26] 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.
• [27] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [28] 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.
• [29] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [30] 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.
• [31] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [32] 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.
• [33] 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.
• [34] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.