Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1BTAJO)

• DOT Name: Zinc finger protein GLI1 (GLI1)
• Synonyms: Glioma-associated oncogene; Oncogene GLI
• Gene Name: GLI1
• Related Disease:
  Ellis-van Creveld syndrome
  Polydactyly of a biphalangeal thumb
  Postaxial polydactyly type A
  Polydactyly, postaxial, type A8
• UniProt ID: GLI1_HUMAN
• PDB ID: 2GLI; 4BLB; 4KMD; 5OM0; 7T91
• Pfam ID: PF00096
• Sequence:
  MFNSMTPPPISSYGEPCCLRPLPSQGAPSVGTEGLSGPPFCHQANLMSGPHSYGPARETN
  SCTEGPLFSSPRSAVKLTKKRALSISPLSDASLDLQTVIRTSPSSLVAFINSRCTSPGGS
  YGHLSIGTMSPSLGFPAQMNHQKGPSPSFGVQPCGPHDSARGGMIPHPQSRGPFPTCQLK
  SELDMLVGKCREEPLEGDMSSPNSTGIQDPLLGMLDGREDLEREEKREPESVYETDCRWD
  GCSQEFDSQEQLVHHINSEHIHGERKEFVCHWGGCSRELRPFKAQYMLVVHMRRHTGEKP
  HKCTFEGCRKSYSRLENLKTHLRSHTGEKPYMCEHEGCSKAFSNASDRAKHQNRTHSNEK
  PYVCKLPGCTKRYTDPSSLRKHVKTVHGPDAHVTKRHRGDGPLPRAPSISTVEPKREREG
  GPIREESRLTVPEGAMKPQPSPGAQSSCSSDHSPAGSAANTDSGVEMTGNAGGSTEDLSS
  LDEGPCIAGTGLSTLRRLENLRLDQLHQLRPIGTRGLKLPSLSHTGTTVSRRVGPPVSLE
  RRSSSSSSISSAYTVSRRSSLASPFPPGSPPENGASSLPGLMPAQHYLLRARYASARGGG
  TSPTAASSLDRIGGLPMPPWRSRAEYPGYNPNAGVTRRASDPAQAADRPAPARVQRFKSL
  GCVHTPPTVAGGGQNFDPYLPTSVYSPQPPSITENAAMDARGLQEEPEVGTSMVGSGLNP
  YMDFPPTDTLGYGGPEGAAAEPYGARGPGSLPLGPGPPTNYGPNPCPQQASYPDPTQETW
  GEFPSHSGLYPGPKALGGTYSQCPRLEHYGQVQVKPEQGCPVGSDSTGLAPCLNAHPSEG
  PPHPQPLFSHYPQPSPPQYLQSGPYTQPPPDYLPSEPRPCLDFDSPTHSTGQLKAQLVCN
  YVQSQQELLWEGGGREDAPAQEPSYQSPKFLGGSQVSPSRAKAPVNTYGPGFGPNLPNHK
  SGSYPTPSPCHENFVVGANRASHRAAAPPRLLPPLPTCYGPLKVGGTNPSCGHPEVGRLG
  GGPALYPPPEGQVCNPLDSLDLDNTQLDFVAILDEPQGLSPPPSHDQRGSSGHTPPPSGP
  PNMAVGNMSVLLRSLPGETEFLNSSA
• Function: Acts as a transcriptional activator. Binds to the DNA consensus sequence 5'-GACCACCCA-3'. Regulates the transcription of specific genes during normal development. Plays a role in craniofacial development and digital development, as well as development of the central nervous system and gastrointestinal tract. Mediates SHH signaling. Plays a role in cell proliferation and differentiation via its role in SHH signaling ; [Isoform 2]: Acts as a transcriptional activator, but activates a different set of genes than isoform 1. Activates expression of CD24, unlike isoform 1. Mediates SHH signaling. Promotes cancer cell migration.
• Tissue Specificity: Detected in testis (at protein level) . Testis, myometrium and fallopian tube. Also expressed in the brain with highest expression in the cerebellum, optic nerve and olfactory tract . Isoform 1 is detected in brain, spleen, pancreas, liver, kidney and placenta; isoform 2 is not detectable in these tissues .
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Hedgehog sig.ling pathway (hsa04340)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway:
  Hedgehog 'off' state (R-HSA-5610787)
  Hedgehog 'on' state (R-HSA-5632684)
  GLI proteins bind promoters of Hh responsive genes to promote transcription (R-HSA-5635851)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ellis-van Creveld syndrome	DISWSKIF	Supportive	Autosomal recessive	[1]
Polydactyly of a biphalangeal thumb	DISX46OZ	Supportive	Autosomal dominant	[2]
Postaxial polydactyly type A	DIS4IIPW	Supportive	Autosomal recessive	[3]
Polydactyly, postaxial, type A8	DISIKM1O	Limited	Unknown	[3]

19 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 Zinc finger protein GLI1 (GLI1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Zinc finger protein GLI1 (GLI1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger protein GLI1 (GLI1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Zinc finger protein GLI1 (GLI1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Zinc finger protein GLI1 (GLI1).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Zinc finger protein GLI1 (GLI1).	[10]
Tofacitinib	DMBS370	Approved	Tofacitinib increases the expression of Zinc finger protein GLI1 (GLI1).	[11]
Vismodegib	DM5IXKQ	Approved	Vismodegib decreases the expression of Zinc finger protein GLI1 (GLI1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Zinc finger protein GLI1 (GLI1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Zinc finger protein GLI1 (GLI1).	[15]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the expression of Zinc finger protein GLI1 (GLI1).	[16]
EMBELIN	DMFZO4Y	Terminated	EMBELIN decreases the expression of Zinc finger protein GLI1 (GLI1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Zinc finger protein GLI1 (GLI1).	[18]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Zinc finger protein GLI1 (GLI1).	[19]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Zinc finger protein GLI1 (GLI1).	[20]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Zinc finger protein GLI1 (GLI1).	[21]
Mepacrine	DMU8L7C	Investigative	Mepacrine decreases the expression of Zinc finger protein GLI1 (GLI1).	[22]
CYCLOPAMINE	DMEM2SW	Investigative	CYCLOPAMINE affects the expression of Zinc finger protein GLI1 (GLI1).	[23]
SAG	DMHOG7W	Investigative	SAG increases the expression of Zinc finger protein GLI1 (GLI1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Zinc finger protein GLI1 (GLI1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Zinc finger protein GLI1 (GLI1).	[14]

References

• [1] GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome. Hum Mol Genet. 2017 Dec 1;26(23):4556-4571. doi: 10.1093/hmg/ddx335.
• [2] A novel homozygous sequence variant in GLI1 underlies first case of autosomal recessive pre-axial polydactyly. Clin Genet. 2019 Apr;95(4):540-541. doi: 10.1111/cge.13495. Epub 2019 Jan 8.
• [3] Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B. Hum Mutat. 2020 Jan;41(1):265-276. doi: 10.1002/humu.23921. Epub 2019 Nov 6.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression. Environ Health. 2017 Jun 14;16(1):59. doi: 10.1186/s12940-017-0267-8.
• [9] Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation. PLoS One. 2013 Jul 8;8(7):e69466. doi: 10.1371/journal.pone.0069466. Print 2013.
• [10] Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells. Acta Biochim Biophys Sin (Shanghai). 2008 Sep;40(9):819-29.
• [11] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [12] Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
• [13] Sonic hedgehog signaling regulates Bcr-Abl expression in human chronic myeloid leukemia cells. Biomed Pharmacother. 2012 Jul;66(5):378-83. doi: 10.1016/j.biopha.2011.12.008. Epub 2012 Feb 16.
• [14] 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.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002. Onco Targets Ther. 2015 Apr 17;8:877-83. doi: 10.2147/OTT.S71034. eCollection 2015.
• [17] Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways. PLoS One. 2014 Apr 2;9(4):e92161.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] Aspartame induces cancer stem cell enrichment through p21, NICD and GLI1 in human PANC-1 pancreas adenocarcinoma cells. Food Chem Toxicol. 2021 Jul;153:112264. doi: 10.1016/j.fct.2021.112264. Epub 2021 May 14.
• [20] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [21] GLI inhibitors overcome Erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin. J Chemother. 2019 May;31(3):141-149. doi: 10.1080/1120009X.2019.1584422. Epub 2019 Apr 14.
• [22] Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and catenin through activation of GSK3. Toxicol Appl Pharmacol. 2017 Sep 1;330:53-64. doi: 10.1016/j.taap.2017.07.008. Epub 2017 Jul 15.
• [23] Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res. 2009 Nov;29(11):4629-32.
• [24] Differential role of Pax6 and its interaction with Shh-Gli1-IDH2 axis in regulation of glioma growth and chemoresistance. J Biochem Mol Toxicol. 2023 Feb;37(2):e23241. doi: 10.1002/jbt.23241. Epub 2022 Oct 7.