Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6AP4V2)

• DOT Name: Zinc finger protein PLAGL2 (PLAGL2)
• Synonyms: Pleiomorphic adenoma-like protein 2
• Gene Name: PLAGL2
• Related Disease:
  Bladder transitional cell carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Laryngeal squamous cell carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Pulmonary emphysema
  Acute myelogenous leukaemia
  Hirschsprung disease
  leukaemia
  Leukemia
• UniProt ID: PLAL2_HUMAN
• Pfam ID: PF00096 ; PF13912
• Sequence:
  MTTFFTSVPPWIQDAKQEEEVGWKLVPRPRGREAESQVKCQCEISGTPFSNGEKLRPHSL
  PQPEQRPYSCPQLHCGKAFASKYKLYRHMATHSAQKPHQCMYCDKMFHRKDHLRNHLQTH
  DPNKEALHCSECGKNYNTKLGYRRHLAMHAASSGDLSCKVCLQTFESTQALLEHLKAHSR
  RVAGGAKEKKHPCDHCDRRFYTRKDVRRHLVVHTGRKDFLCQYCAQRFGRKDHLTRHVKK
  SHSQELLKIKTEPVDMLGLLSCSSTVSVKEELSPVLCMASRDVMGTKAFPGMLPMGMYGA
  HIPTMPSTGVPHSLVHNTLPMGMSYPLESSPISSPAQLPPKYQLGSTSYLPDKLPKVEVD
  SFLAELPGSLSLSSAEPQPASPQPAAAAALLDEALLAKSPANLSEALCAANVDFSHLLGF
  LPLNLPPCNPPGATGGLVMGYSQAEAQPLLTTLQAQPQDSPGAGGPLNFGPLHSLPPVFT
  SGLSSTTLPRFHQAFQ
• Function: Shows weak transcriptional activatory activity.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[4]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[4]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[5]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[6]
Lung cancer	DISCM4YA	moderate	Altered Expression	[6]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[6]
Lung neoplasm	DISVARNB	moderate	Altered Expression	[6]
Pulmonary emphysema	DIS5M7HZ	moderate	Altered Expression	[6]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[7]
Hirschsprung disease	DISUUSM1	Limited	Biomarker	[2]
leukaemia	DISS7D1V	Limited	Altered Expression	[7]
Leukemia	DISNAKFL	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Zinc finger protein PLAGL2 (PLAGL2).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger protein PLAGL2 (PLAGL2).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Zinc finger protein PLAGL2 (PLAGL2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Zinc finger protein PLAGL2 (PLAGL2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger protein PLAGL2 (PLAGL2).	[22]

References

• [1] Expression of PLAGL2 in bladder urothelial carcinoma and its relationship to lymph node metastasis and survival.Sci Rep. 2018 Apr 16;8(1):6044. doi: 10.1038/s41598-018-24526-5.
• [2] PLAGL2 promotes epithelial-mesenchymal transition and mediates colorectal cancer metastasis via -catenin-dependent regulation of ZEB1.Br J Cancer. 2020 Feb;122(4):578-589. doi: 10.1038/s41416-019-0679-z. Epub 2019 Dec 12.
• [3] MiR-449a suppresses cell migration and invasion by targeting PLAGL2 in breast cancer.Pathol Res Pract. 2018 May;214(5):790-795. doi: 10.1016/j.prp.2017.12.012. Epub 2018 Jan 5.
• [4] MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways.Oncogene. 2019 Aug;38(32):6035-6050. doi: 10.1038/s41388-019-0860-0. Epub 2019 Jul 5.
• [5] Regulation of cell proliferation and migration in gallbladder cancer by zinc finger X-chromosomal protein.Gene. 2013 Oct 10;528(2):261-6. doi: 10.1016/j.gene.2013.06.064. Epub 2013 Jul 13.
• [6] Pleiomorphic adenoma gene-like 2 expression is associated with the development of lung adenocarcinoma and emphysema.Lung Cancer. 2011 Oct;74(1):12-24. doi: 10.1016/j.lungcan.2011.02.006. Epub 2011 Mar 11.
• [7] The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells.Leukemia. 2011 Apr;25(4):655-62. doi: 10.1038/leu.2010.301. Epub 2011 Jan 25.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] 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.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.