Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBDNB26)

• DOT Name: Zinc finger protein GLIS1 (GLIS1)
• Synonyms: GLI-similar 1
• Gene Name: GLIS1
• Related Disease:
  Acute megakaryoblastic leukemia
  Advanced cancer
  Alzheimer disease
  Fibrolamellar liver cancer
  Late-onset Parkinson disease
  Neoplasm
  Parkinson disease
  Psoriasis
  Squamous cell carcinoma
  Thyroid tumor
  Acute myelogenous leukaemia
  Mitral valve prolapse
• UniProt ID: GLIS1_HUMAN
• Pfam ID: PF00096
• Sequence:
  MAEARTSLSAHCRGPLATGLHPDLDLPGRSLATPAPSCYLLGSEPSSGLGLQPETHLPEG
  SLKRCCVLGLPPTSPASSSPCASSDVTSIIRSSQTSLVTCVNGLRSPPLTGDLGGPSKRA
  RPGPASTDSHEGSLQLEACRKASFLKQEPADEFSELFGPHQQGLPPPYPLSQLPPGPSLG
  GLGLGLAGRVVAGRQACRWVDCCAAYEQQEELVRHIEKSHIDQRKGEDFTCFWAGCVRRY
  KPFNARYKLLIHMRVHSGEKPNKCMFEGCSKAFSRLENLKIHLRSHTGEKPYLCQHPGCQ
  KAFSNSSDRAKHQRTHLDTKPYACQIPGCSKRYTDPSSLRKHVKAHSAKEQQVRKKLHAG
  PDTEADVLTECLVLQQLHTSTQLAASDGKGGCGLGQELLPGVYPGSITPHNGLASGLLPP
  AHDVPSRHHPLDATTSSHHHLSPLPMAESTRDGLGPGLLSPIVSPLKGLGPPPLPPSSQS
  HSPGGQPFPTLPSKPSYPPFQSPPPPPLPSPQGYQGSFHSIQSCFPYGDCYRMAEPAAGG
  DGLVGETHGFNPLRPNGYHSLSTPLPATGYEALAEASCPTALPQQPSEDVVSSGPEDCGF
  FPNGAFDHCLGHIPSIYTDT
• Function: Acts both as a repressor and an activator of transcription. Binds to the consensus sequence 5'-GACCACCCAC-3'. By controlling the expression of genes involved in cell differentiation inhibits the lineage commitment of multipotent cells. Prevents, for instance, the differentiation of multipotent mesenchymal cells into adipocyte and osteoblast.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Fibrolamellar liver cancer	DISUDA2P	Strong	Biomarker	[1]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[3]
Psoriasis	DIS59VMN	Strong	Altered Expression	[4]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[4]
Thyroid tumor	DISLVKMD	Strong	Genetic Variation	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[6]
Mitral valve prolapse	DISNCHQ3	Limited	Biomarker	[7]

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 Zinc finger protein GLIS1 (GLIS1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Zinc finger protein GLIS1 (GLIS1).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger protein GLIS1 (GLIS1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Zinc finger protein GLIS1 (GLIS1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Zinc finger protein GLIS1 (GLIS1).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Zinc finger protein GLIS1 (GLIS1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Zinc finger protein GLIS1 (GLIS1).	[14]

References

• [1] Emerging Roles of GLI-Similar Krppel-like Zinc Finger Transcription Factors in Leukemia and Other Cancers.Trends Cancer. 2019 Sep;5(9):547-557. doi: 10.1016/j.trecan.2019.07.005. Epub 2019 Aug 20.
• [2] Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.Acta Neuropathol. 2017 May;133(5):839-856. doi: 10.1007/s00401-017-1685-y. Epub 2017 Feb 28.
• [3] GLIS1 rs797906: an increased risk factor for late-onset Parkinson's disease in the Han Chinese population.Eur Neurol. 2012;68(2):89-92. doi: 10.1159/000337955. Epub 2012 Jul 3.
• [4] Regulatory role for Krppel-like zinc-finger protein Gli-similar 1 (Glis1) in PMA-treated and psoriatic epidermis.J Invest Dermatol. 2006 Jan;126(1):49-60. doi: 10.1038/sj.jid.5700018.
• [5] PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid.Mod Pathol. 2019 Dec;32(12):1734-1743. doi: 10.1038/s41379-019-0313-x. Epub 2019 Jul 4.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] Genome-Wide Association Study-Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse.Circ Genom Precis Med. 2019 May;12(5):e002497. doi: 10.1161/CIRCGEN.119.002497.
• [8] 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.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] 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.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.