Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7G9JG6)

• DOT Name: Protein flightless-1 homolog (FLII)
• Gene Name: FLII
• Related Disease:
  Acute erythroid leukemia
  Acute lymphocytic leukaemia
  Astrocytoma
  Autoimmune disease
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Desmoplastic small round cell tumor
  Esophageal squamous cell carcinoma
  Ewing sarcoma
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Leukemia
  Lupus
  Lymphoma
  Malignant soft tissue neoplasm
  Myelodysplastic syndrome
  Non-alcoholic fatty liver disease
  Osteoporosis
  Osteosarcoma
  Primitive neuroectodermal tumor
  Prostate cancer
  Prostate carcinoma
  Sarcoma
  Smith-Magenis syndrome
  Systemic lupus erythematosus
  Systemic sclerosis
  Thrombocytopenia
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vascular disease
  Carcinoma
  Nephropathy
  Neuroblastoma
  Plasma cell myeloma
  Small lymphocytic lymphoma
  Small-cell lung cancer
  Squamous cell carcinoma
  Fatty liver disease
  Hepatocellular carcinoma
  leukaemia
  Melanoma
  Non-insulin dependent diabetes
  Wilms tumor
• UniProt ID: FLII_HUMAN
• Pfam ID: PF00626 ; PF00560 ; PF12799 ; PF13855
• Sequence:
  MEATGVLPFVRGVDLSGNDFKGGYFPENVKAMTSLRWLKLNRTGLCYLPEELAALQKLEH
  LSVSHNNLTTLHGELSSLPSLRAIVARANSLKNSGVPDDIFKLDDLSVLDLSHNQLTECP
  RELENAKNMLVLNLSHNSIDTIPNQLFINLTDLLYLDLSENRLESLPPQMRRLVHLQTLV
  LNGNPLLHAQLRQLPAMTALQTLHLRSTQRTQSNLPTSLEGLSNLADVDLSCNDLTRVPE
  CLYTLPSLRRLNLSSNQITELSLCIDQWVHVETLNLSRNQLTSLPSAICKLSKLKKLYLN
  SNKLDFDGLPSGIGKLTNLEEFMAANNNLELVPESLCRCPKLRKLVLNKNHLVTLPEAIH
  FLTEIEVLDVRENPNLVMPPKPADRAAEWYNIDFSLQNQLRLAGASPATVAAAAAAGSGP
  KDPMARKMRLRRRKDSAQDDQAKQVLKGMSDVAQEKNKKQEESADARAPSGKVRRWDQGL
  EKPRLDYSEFFTEDVGQLPGLTIWQIENFVPVLVEEAFHGKFYEADCYIVLKTFLDDSGS
  LNWEIYYWIGGEATLDKKACSAIHAVNLRNYLGAECRTVREEMGDESEEFLQVFDNDISY
  IEGGTASGFYTVEDTHYVTRMYRVYGKKNIKLEPVPLKGTSLDPRFVFLLDRGLDIYVWR
  GAQATLSSTTKARLFAEKINKNERKGKAEITLLVQGQELPEFWEALGGEPSEIKKHVPED
  FWPPQPKLYKVGLGLGYLELPQINYKLSVEHKQRPKVELMPRMRLLQSLLDTRCVYILDC
  WSDVFIWLGRKSPRLVRAAALKLGQELCGMLHRPRHATVSRSLEGTEAQVFKAKFKNWDD
  VLTVDYTRNAEAVLQSPGLSGKVKRDAEKKDQMKADLTALFLPRQPPMSLAEAEQLMEEW
  NEDLDGMEGFVLEGKKFARLPEEEFGHFYTQDCYVFLCRYWVPVEYEEEEKKEDKEEKAE
  GKEGEEATAEAEEKQPEEDFQCIVYFWQGREASNMGWLTFTFSLQKKFESLFPGKLEVVR
  MTQQQENPKFLSHFKRKFIIHRGKRKAVQGAQQPSLYQIRTNGSALCTRCIQINTDSSLL
  NSEFCFILKVPFESEDNQGIVYAWVGRASDPDEAKLAEDILNTMFDTSYSKQVINEGEEP
  ENFFWVGIGAQKPYDDDAEYMKHTRLFRCSNEKGYFAVTEKCSDFCQDDLADDDIMLLDN
  GQEVYMWVGTQTSQVEIKLSLKACQVYIQHMRSKEHERPRRLRLVRKGNEQHAFTRCFHA
  WSAFCKALA
• Function: May play a role as coactivator in transcriptional activation by hormone-activated nuclear receptors (NR) and acts in cooperation with NCOA2 and CARM1. Involved in estrogen hormone signaling. Involved in early embryonic development. May play a role in regulation of cytoskeletal rearrangements involved in cytokinesis and cell migration, by inhibiting Rac1-dependent paxillin phosphorylation.
• Tissue Specificity: Strongest expression in skeletal muscle with high expression also in the heart and lung.

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Desmoplastic small round cell tumor	DISLI2ME	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[9]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[10]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Biomarker	[11]
Leukemia	DISNAKFL	Strong	Altered Expression	[12]
Lupus	DISOKJWA	Strong	Biomarker	[4]
Lymphoma	DISN6V4S	Strong	Biomarker	[13]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[14]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[15]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[16]
Osteoporosis	DISF2JE0	Strong	Biomarker	[17]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[14]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Altered Expression	[18]
Prostate cancer	DISF190Y	Strong	Altered Expression	[19]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[19]
Sarcoma	DISZDG3U	Strong	Biomarker	[14]
Smith-Magenis syndrome	DISG4G6X	Strong	Genetic Variation	[20]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[4]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[21]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[22]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[23]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Vascular disease	DISVS67S	Strong	Altered Expression	[21]
Carcinoma	DISH9F1N	moderate	Altered Expression	[24]
Nephropathy	DISXWP4P	moderate	Biomarker	[25]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[26]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[13]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[13]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[27]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[28]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[29]
leukaemia	DISS7D1V	Limited	Genetic Variation	[30]
Melanoma	DIS1RRCY	Limited	Biomarker	[31]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[23]
Wilms tumor	DISB6T16	Limited	Biomarker	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	Protein flightless-1 homolog (FLII) decreases the response to substance of Capecitabine.	[43]

2 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 Protein flightless-1 homolog (FLII).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein flightless-1 homolog (FLII).	[40]

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 Protein flightless-1 homolog (FLII).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein flightless-1 homolog (FLII).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein flightless-1 homolog (FLII).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein flightless-1 homolog (FLII).	[37]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein flightless-1 homolog (FLII).	[38]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Protein flightless-1 homolog (FLII).	[39]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Protein flightless-1 homolog (FLII).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein flightless-1 homolog (FLII).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein flightless-1 homolog (FLII).	[42]

References

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• [2] Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma.PLoS One. 2013 May 7;8(5):e62346. doi: 10.1371/journal.pone.0062346. Print 2013.
• [3] Overexpression of Fli-1 in astrocytoma is associated with poor prognosis.Oncotarget. 2017 Apr 25;8(17):29174-29186. doi: 10.18632/oncotarget.16303.
• [4] Fli-1, a Functional Factor Performed in Autoimmune Lupus.Inflammation. 2016 Feb;39(1):493-498. doi: 10.1007/s10753-015-0257-3.
• [5] Transcriptional regulatory networks in human lung adenocarcinoma.Mol Med Rep. 2012 Nov;6(5):961-6. doi: 10.3892/mmr.2012.1034. Epub 2012 Aug 14.
• [6] Functional roles of Fli-1, a member of the Ets family of transcription factors, in human breast malignancy.Cancer Sci. 2007;98(11):1775-84. doi: 10.1111/j.1349-7006.2007.00598.x.
• [7] Flightless I homolog negatively regulates ChREBP activity in cancer cells.Int J Biochem Cell Biol. 2013 Nov;45(11):2688-97. doi: 10.1016/j.biocel.2013.09.004. Epub 2013 Sep 17.
• [8] A t (11; 22) (p13; q12) EWS-WT 1 positive desmoplastic small round cell tumor of the maxilla: an unusual case indicating the role of molecular diagnosis in round cell sarcomas.J Postgrad Med. 2010 Jul-Sep;56(3):201-5. doi: 10.4103/0022-3859.68628.
• [9] FLI-06 suppresses proliferation, induces apoptosis and cell cycle arrest by targeting LSD1 and Notch pathway in esophageal squamous cell carcinoma cells.Biomed Pharmacother. 2018 Nov;107:1370-1376. doi: 10.1016/j.biopha.2018.08.140. Epub 2018 Aug 31.
• [10] Ewing's sarcoma in the spinal canal of T12-L3: A case report and review of the literature.Oncol Lett. 2019 Dec;18(6):6157-6163. doi: 10.3892/ol.2019.10958. Epub 2019 Oct 3.
• [11] Primitive Neuroectodermal Tumors of the Female Genital Tract: A Morphologic, Immunohistochemical, and Molecular Study of 19 Cases.Am J Surg Pathol. 2017 Jun;41(6):761-772. doi: 10.1097/PAS.0000000000000831.
• [12] Fli-1 promotes proliferation and upregulates NANOGP8 expression in T-lymphocyte leukemia cells.Biochimie. 2020 Jan;168:1-9. doi: 10.1016/j.biochi.2019.10.005. Epub 2019 Oct 15.
• [13] Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.FEBS J. 2018 Dec;285(24):4631-4645. doi: 10.1111/febs.14690. Epub 2018 Nov 20.
• [14] FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma.Appl Immunohistochem Mol Morphol. 2011 May;19(3):233-8. doi: 10.1097/PAI.0b013e3181fd6697.
• [15] Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.Blood. 2011 Oct 27;118(17):4666-73. doi: 10.1182/blood-2010-12-324715. Epub 2011 Aug 26.
• [16] Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes.Diabetes Obes Metab. 2020 Mar;22(3):393-403. doi: 10.1111/dom.13907. Epub 2019 Dec 14.
• [17] The relationship between fatty liver index and bone mineral density in Koreans: KNHANES 2010-2011.Osteoporos Int. 2018 Jan;29(1):181-190. doi: 10.1007/s00198-017-4257-z. Epub 2017 Oct 19.
• [18] ZBTB16: A new biomarker for primitive neuroectodermal tumor element / Ewing sarcoma.Pathol Res Pract. 2019 Oct;215(10):152536. doi: 10.1016/j.prp.2019.152536. Epub 2019 Jul 13.
• [19] Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling.Clin Cancer Res. 2016 Mar 15;22(6):1531-44. doi: 10.1158/1078-0432.CCR-15-1632. Epub 2015 Nov 2.
• [20] Diagnostic FISH probes for del(17)(p11.2p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene.Am J Med Genet A. 2005 Jan 30;132A(3):278-82. doi: 10.1002/ajmg.a.30461.
• [21] Endothelin receptor blockade ameliorates vascular fragility in endothelial cell-specific Fli-1-knockout mice by increasing Fli-1 DNA binding ability.Arthritis Rheumatol. 2015 May;67(5):1335-44. doi: 10.1002/art.39062.
• [22] Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity. 2000 Aug;13(2):167-77. doi: 10.1016/s1074-7613(00)00017-0.
• [23] Occurrence over time and regression of nonalcoholic fatty liver disease in type 2 diabetes.Diabetes Metab Res Rev. 2017 May;33(4). doi: 10.1002/dmrr.2878. Epub 2017 Jan 27.
• [24] IMP3 as a prognostic biomarker in patients with malignant peritoneal mesothelioma.Hum Pathol. 2018 Nov;81:138-147. doi: 10.1016/j.humpath.2018.07.003. Epub 2018 Jul 18.
• [25] An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes.Mol Cell Biol. 1995 Dec;15(12):6961-70. doi: 10.1128/MCB.15.12.6961.
• [26] Anaplastic large cell neuroblastoma.Pediatr Dev Pathol. 2009 Jan-Feb;12(1):1-5. doi: 10.2350/07-04-0255.1.
• [27] MYCN-mediated regulation of the HES1 promoter enhances the chemoresistance of small-cell lung cancer by modulating apoptosis.Am J Cancer Res. 2019 Sep 1;9(9):1938-1956. eCollection 2019.
• [28] Friend leukaemia insertion (Fli)-1 is a prediction marker candidate for radiotherapy resistant oral squamous cell carcinoma.Int J Oral Maxillofac Surg. 2010 Nov;39(11):1115-9. doi: 10.1016/j.ijom.2010.02.027. Epub 2010 Aug 14.
• [29] Fli? promotes metastasis by regulating MMP2 signaling in hepatocellular carcinoma.Mol Med Rep. 2018 Jan;17(1):1986-1992. doi: 10.3892/mmr.2017.8047. Epub 2017 Nov 14.
• [30] The poor prognosis of the primary gastric epithelioid angiosarcoma: A case report.Medicine (Baltimore). 2018 Apr;97(15):e0287. doi: 10.1097/MD.0000000000010287.
• [31] Aberrant expression of FLI-1 in melanoma.J Cutan Pathol. 2017 Sep;44(9):790-793. doi: 10.1111/cup.12979. Epub 2017 Jul 10.
• [32] Immunohistochemistry of primary malignant neuroepithelial tumors of the kidney: a potential source of confusion? A study of 30 cases from the National Wilms Tumor Study Pathology Center.Hum Pathol. 2007 Feb;38(2):205-11. doi: 10.1016/j.humpath.2006.08.026. Epub 2006 Nov 28.
• [33] 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.
• [34] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [35] 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.
• [36] 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.
• [37] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [38] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [39] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [40] 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.
• [41] 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.
• [42] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [43] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.