Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOUUV1X)

DOT Name	Zinc finger protein GLIS2 (GLIS2)
Synonyms	GLI-similar 2; Neuronal Krueppel-like protein
Gene Name	GLIS2
Related Disease	Acute megakaryoblastic leukemia ( ) Acute monocytic leukemia ( ) Acute myelogenous leukaemia ( ) Adult glioblastoma ( ) Advanced cancer ( ) Autosomal dominant polycystic kidney disease ( ) B-cell lymphoma ( ) B-cell neoplasm ( ) Bardet biedl syndrome ( ) Caroli disease ( ) Childhood acute megakaryoblastic leukemia ( ) Ciliopathy ( ) Fibrolamellar liver cancer ( ) Gastrointestinal stromal tumour ( ) Glioblastoma multiforme ( ) Hepatocellular carcinoma ( ) Hepatosplenic T-cell lymphoma ( ) Kidney failure ( ) leukaemia ( ) Leukemia ( ) Lymphoma ( ) Mantle cell lymphoma ( ) Myelodysplastic syndrome ( ) Nephronophthisis 7 ( ) Nephropathy ( ) Normal pressure hydrocephalus ( ) Primary cutaneous peripheral T-cell lymphoma not otherwise specified ( ) Renal fibrosis ( ) T-cell lymphoma ( ) Neonatal diabetes mellitus ( ) Nephronophthisis ( ) Nephronophthisis 1 ( ) Adult lymphoma ( ) Chronic kidney disease ( ) Classic Hodgkin lymphoma ( ) Gastric cancer ( ) Lymphoid leukemia ( ) Neoplasm ( ) Pediatric lymphoma ( ) Stomach cancer ( ) T-cell acute lymphoblastic leukaemia ( ) T-cell leukaemia ( )
UniProt ID	GLIS2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00096
Sequence	MHSLDEPLDLKLSITKLRAAREKRERTLGVVRPRALHRELGLVDDSPTPGSPGSPPSGFL LNSKFPEKVEGRFSAAPLVDLSLSPPSGLDSPNGSSSLSPERQGNGDLPPVPSASDFQPL RYLDGVPSSFQFFLPLGSGGALHLPASSFLTPPKDKCLSPDLPLPKQLVCRWAKCNQLFE LLQDLVDHVNDYHVKPEKDAGYCCHWEGCARHGRGFNARYKMLIHIRTHTNEKPHRCPTC SKSFSRLENLKIHNRSHTGEKPYVCPYEGCNKRYSNSSDRFKHTRTHYVDKPYYCKMPGC HKRYTDPSSLRKHIKAHGHFVSHEQQELLQLRPPPKPPLPAPDGGPYVSGAQIIIPNPAA LFGGPGLPGLPLPLAPGPLDLSALACGNGGGSGGGGGMGPGLPGPVLPLNLAKNPLLPSP FGAGGLGLPVVSLLAGAAGGKAEGEKGRGSVPTRALGMEGHKTPLERTESSCSRPSPDGL PLLPGTVLDLSTGVNSAASSPEALAPGWVVIPPGSVLLKPAVVN
Function	Can act either as a transcriptional repressor or as a transcriptional activator, depending on the cell context. Acts as a repressor of the Hedgehog signaling pathway. Represses the Hedgehog-dependent expression of Wnt4. Necessary to maintain the differentiated epithelial phenotype in renal cells through the inhibition of SNAI1, which itself induces the epithelial-to-mesenchymal transition. Represses transcriptional activation mediated by CTNNB1 in the Wnt signaling pathway. May act by recruiting the corepressors CTBP1 and HDAC3. May be involved in neuron differentiation.
Tissue Specificity	Expressed at high levels in kidney and at low levels in heart, lung and placenta. Expressed in colon.

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute megakaryoblastic leukemia	DIS0JX3M	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[6]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[7]
B-cell neoplasm	DISVY326	Strong	Biomarker	[8]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[9]
Caroli disease	DISXQYMX	Strong	Genetic Variation	[10]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Strong	Biomarker	[11]
Ciliopathy	DIS10G4I	Strong	Altered Expression	[9]
Fibrolamellar liver cancer	DISUDA2P	Strong	Genetic Variation	[5]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Hepatosplenic T-cell lymphoma	DIS7KMY9	Strong	Biomarker	[14]
Kidney failure	DISOVQ9P	Strong	Biomarker	[15]
leukaemia	DISS7D1V	Strong	Altered Expression	[13]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Lymphoma	DISN6V4S	Strong	Biomarker	[16]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[18]
Nephronophthisis 7	DIS6LSO8	Strong	Autosomal recessive	[19]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[20]
Normal pressure hydrocephalus	DISOEFO9	Strong	Genetic Variation	[21]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[14]
Renal fibrosis	DISMHI3I	Strong	Genetic Variation	[22]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[14]
Neonatal diabetes mellitus	DISFHF9K	moderate	Genetic Variation	[23]
Nephronophthisis	DISXU4HY	moderate	Biomarker	[24]
Nephronophthisis 1	DIS7QNQ3	Supportive	Autosomal recessive	[19]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[25]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[22]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Altered Expression	[26]
Gastric cancer	DISXGOUK	Limited	Biomarker	[27]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[25]
Neoplasm	DISZKGEW	Limited	Biomarker	[28]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[25]
Stomach cancer	DISKIJSX	Limited	Biomarker	[27]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Genetic Variation	[29]
T-cell leukaemia	DISJ6YIF	Limited	Biomarker	[26]
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⏷ Show the Full List of 42 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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 GLIS2 (GLIS2).	[30]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc finger protein GLIS2 (GLIS2).	[35]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger protein GLIS2 (GLIS2).	[39]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Zinc finger protein GLIS2 (GLIS2).	[42]
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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 Zinc finger protein GLIS2 (GLIS2).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein GLIS2 (GLIS2).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc finger protein GLIS2 (GLIS2).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Zinc finger protein GLIS2 (GLIS2).	[34]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Zinc finger protein GLIS2 (GLIS2).	[36]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Zinc finger protein GLIS2 (GLIS2).	[37]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Zinc finger protein GLIS2 (GLIS2).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Zinc finger protein GLIS2 (GLIS2).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger protein GLIS2 (GLIS2).	[41]
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⏷ Show the Full List of 9 Drug(s)

References

1	Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study.Clin Cancer Res. 2020 Feb 1;26(3):726-737. doi: 10.1158/1078-0432.CCR-19-1800. Epub 2019 Nov 12.
2	Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells.Blood. 2018 Apr 19;131(16):1833-1845. doi: 10.1182/blood-2017-05-787226. Epub 2018 Jan 25.
3	CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity.Br J Haematol. 2019 Feb;184(3):337-347. doi: 10.1111/bjh.15725. Epub 2018 Dec 28.
4	CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.Sci Rep. 2015 Jul 9;5:11483. doi: 10.1038/srep11483.
5	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.
6	Parallel analysis of mRNA and microRNA microarray profiles to explore functional regulatory patterns in polycystic kidney disease: using PKD/Mhm rat model.PLoS One. 2013;8(1):e53780. doi: 10.1371/journal.pone.0053780. Epub 2013 Jan 10.
7	Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL.PLoS One. 2019 May 29;14(5):e0216898. doi: 10.1371/journal.pone.0216898. eCollection 2019.
8	Deregulated NKL Homeobox Genes in B-Cell Lymphoma.Cancers (Basel). 2019 Nov 26;11(12):1874. doi: 10.3390/cancers11121874.
9	Interaction with the Bardet-Biedl gene product TRIM32/BBS11 modifies the half-life and localization of Glis2/NPHP7.J Biol Chem. 2014 Mar 21;289(12):8390-401. doi: 10.1074/jbc.M113.534024. Epub 2014 Feb 5.
10	Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013 Aug;132(8):865-84. doi: 10.1007/s00439-013-1297-0. Epub 2013 Apr 5.
11	ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.Cancer Cell. 2017 Mar 13;31(3):452-465. doi: 10.1016/j.ccell.2017.02.006.
12	Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
13	hIL-15-gene modified human natural killer cells (NKL-IL15) exhibit anti-human leukemia functions.J Cancer Res Clin Oncol. 2018 Jul;144(7):1279-1288. doi: 10.1007/s00432-018-2654-0. Epub 2018 May 8.
14	Deregulated expression of NKL homeobox genes in T-cell lymphomas.Oncotarget. 2019 May 14;10(35):3227-3247. doi: 10.18632/oncotarget.26929. eCollection 2019 May 14.
15	Kruppel-like zinc finger protein Glis2 is essential for the maintenance of normal renal functions.Mol Cell Biol. 2008 Apr;28(7):2358-67. doi: 10.1128/MCB.01722-07. Epub 2008 Jan 28.
16	NKL homeobox gene activities in B-cell development and lymphomas.PLoS One. 2018 Oct 11;13(10):e0205537. doi: 10.1371/journal.pone.0205537. eCollection 2018.
17	Oncogenic deregulation of NKL homeobox gene MSX1 in mantle cell lymphoma.Leuk Lymphoma. 2014 Aug;55(8):1893-903. doi: 10.3109/10428194.2013.864762. Epub 2014 Feb 17.
18	NKL homeobox gene activities in normal and malignant myeloid cells.PLoS One. 2019 Dec 11;14(12):e0226212. doi: 10.1371/journal.pone.0226212. eCollection 2019.
19	Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet. 2007 Aug;39(8):1018-24. doi: 10.1038/ng2072. Epub 2007 Jul 8.
20	SUMOylation Blocks the Ubiquitin-Mediated Degradation of the Nephronophthisis Gene Product Glis2/NPHP7.PLoS One. 2015 Jun 17;10(6):e0130275. doi: 10.1371/journal.pone.0130275. eCollection 2015.
21	The C175R mutation alters nuclear localization and transcriptional activity of the nephronophthisis NPHP7 gene product.Eur J Hum Genet. 2016 May;24(5):774-8. doi: 10.1038/ejhg.2015.199. Epub 2015 Sep 16.
22	Identification of nuclear localization, DNA binding, and transactivating mechanisms of Kruppel-like zinc finger protein Gli-similar 2 (Glis2).J Biol Chem. 2011 Feb 11;286(6):4749-59. doi: 10.1074/jbc.M110.165951. Epub 2010 Dec 2.
23	Gli-similar proteins: their mechanisms of action, physiological functions, and roles in disease.Vitam Horm. 2012;88:141-71. doi: 10.1016/B978-0-12-394622-5.00007-9.
24	Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis.Am J Pathol. 2020 Jan;190(1):176-189. doi: 10.1016/j.ajpath.2019.09.013. Epub 2019 Oct 30.
25	Agranular CD4+CD56+ blastic natural killer leukemia/lymphoma.Ann Hematol. 2001 Apr;80(4):228-31. doi: 10.1007/s002770000257.
26	Aberrant expression of NKL homeobox gene HLX in Hodgkin lymphoma.Oncotarget. 2018 Feb 16;9(18):14338-14353. doi: 10.18632/oncotarget.24512. eCollection 2018 Mar 6.
27	GLIS2 redundancy causes chemoresistance and poor prognosis of gastric cancer based on coexpression network analysis.Oncol Rep. 2019 Jan;41(1):191-201. doi: 10.3892/or.2018.6794. Epub 2018 Oct 15.
28	NKL homeobox gene MSX1 acts like a tumor suppressor in NK-cell leukemia.Oncotarget. 2017 Jun 21;8(40):66815-66832. doi: 10.18632/oncotarget.18609. eCollection 2017 Sep 15.
29	TCR rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome.Leukemia. 2018 Jan;32(1):61-71. doi: 10.1038/leu.2017.176. Epub 2017 Jun 8.
30	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.
31	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.
32	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.
33	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
34	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.
35	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.
36	Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
37	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.
38	Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
39	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.
40	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.
41	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.
42	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.