Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZAO900)

• DOT Name: Zinc finger protein PLAGL1 (PLAGL1)
• Synonyms: Lost on transformation 1; LOT-1; Pleiomorphic adenoma-like protein 1; Tumor suppressor ZAC
• Gene Name: PLAGL1
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Gastric adenocarcinoma
  Hemangioblastoma
  Acromegaly
  B-cell lymphoma
  Basal cell carcinoma
  Beckwith-Wiedemann syndrome
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chondrosarcoma
  Chorioamnionitis
  Colorectal carcinoma
  Diabetes mellitus, transient neonatal, 1
  Epithelial ovarian cancer
  Fetal growth restriction
  Gastric cancer
  Head-neck squamous cell carcinoma
  Hydatidiform mole
  Hydatidiform mole, recurrent, 1
  Hyperglycemia
  Non-insulin dependent diabetes
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Pheochromocytoma
  Pituitary gland disorder
  Retinoblastoma
  Silver-Russell syndrome
  Stomach cancer
  Ventricular septal defect
  Clear cell renal carcinoma
  Metastatic malignant neoplasm
  Osteoarthritis
  Transient neonatal diabetes mellitus
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Lateral meningocele syndrome
  Limb-mammary syndrome
  Neoplasm
  Recessive X-linked ichthyosis
  Sarcoma
  Small lymphocytic lymphoma
  Soft tissue sarcoma
  Squamous cell carcinoma
  Type-1/2 diabetes
• UniProt ID: PLAL1_HUMAN
• Pfam ID: PF00096
• Sequence:
  MATFPCQLCGKTFLTLEKFTIHNYSHSRERPYKCVQPDCGKAFVSRYKLMRHMATHSPQK
  SHQCAHCEKTFNRKDHLKNHLQTHDPNKMAFGCEECGKKYNTMLGYKRHLALHAASSGDL
  TCGVCALELGSTEVLLDHLKAHAEEKPPSGTKEKKHQCDHCERCFYTRKDVRRHLVVHTG
  CKDFLCQFCAQRFGRKDHLTRHTKKTHSQELMKESLQTGDLLSTFHTISPSFQLKAAALP
  PFPLGASAQNGLASSLPAEVHSLTLSPPEQAAQPMQPLPESLASLHPSVSPGSPPPPLPN
  HKYNTTSTSYSPLASLPLKADTKGFCNISLFEDLPLQEPQSPQKLNPGFDLAKGNAGKVN
  LPKELPADAVNLTIPASLDLSPLLGFWQLPPPATQNTFGNSTLALGPGESLPHRLSCLGQ
  QQQEPPLAMGTVSLGQLPLPPIPHVFSAGTGSAILPHFHHAFR
• Function: Acts as a transcriptional activator. Involved in the transcriptional regulation of type 1 receptor for pituitary adenylate cyclase-activating polypeptide.
• Reactome Pathway: TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain (R-HSA-6804115)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[2]
Gastric adenocarcinoma	DISWWLTC	Definitive	Genetic Variation	[1]
Hemangioblastoma	DIS1EAZC	Definitive	Altered Expression	[3]
Acromegaly	DISCC73U	Strong	Altered Expression	[4]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[5]
Basal cell carcinoma	DIS7PYN3	Strong	Altered Expression	[6]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[9]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[10]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[11]
Chorioamnionitis	DISL1D9U	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[12]
Diabetes mellitus, transient neonatal, 1	DISFUOL2	Strong	Altered Expression	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[9]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[14]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[15]
Hydatidiform mole	DISKNP7O	Strong	Biomarker	[16]
Hydatidiform mole, recurrent, 1	DISXUJWE	Strong	Biomarker	[16]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[13]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[17]
Obesity	DIS47Y1K	Strong	Genetic Variation	[18]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[9]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[9]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[3]
Pituitary gland disorder	DIS7XB48	Strong	Altered Expression	[19]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[20]
Silver-Russell syndrome	DISSVJ1D	Strong	Biomarker	[21]
Stomach cancer	DISKIJSX	Strong	Biomarker	[22]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[23]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[24]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[24]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[25]
Transient neonatal diabetes mellitus	DIST826V	Supportive	Autosomal dominant	[26]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[27]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[27]
Lateral meningocele syndrome	DISG74RP	Limited	Altered Expression	[28]
Limb-mammary syndrome	DIS7H4FP	Limited	Altered Expression	[28]
Neoplasm	DISZKGEW	Limited	Biomarker	[29]
Recessive X-linked ichthyosis	DISZY56W	Limited	Posttranslational Modification	[28]
Sarcoma	DISZDG3U	Limited	Posttranslational Modification	[28]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[30]
Soft tissue sarcoma	DISSN8XB	Limited	Posttranslational Modification	[28]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[6]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Zinc finger protein PLAGL1 (PLAGL1) affects the response to substance of Mitoxantrone.	[53]

5 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 PLAGL1 (PLAGL1).	[32]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc finger protein PLAGL1 (PLAGL1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Zinc finger protein PLAGL1 (PLAGL1).	[45]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger protein PLAGL1 (PLAGL1).	[46]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Zinc finger protein PLAGL1 (PLAGL1).	[49]

16 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 PLAGL1 (PLAGL1).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Zinc finger protein PLAGL1 (PLAGL1).	[35]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[37]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[38]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Zinc finger protein PLAGL1 (PLAGL1).	[39]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[40]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[27]
Riboflavin	DM8YMWE	Approved	Riboflavin affects the expression of Zinc finger protein PLAGL1 (PLAGL1).	[42]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[43]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[47]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[48]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[50]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[51]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Zinc finger protein PLAGL1 (PLAGL1).	[52]

References

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• [2] DNA methylation at imprint regulatory regions in preterm birth and infection.Am J Obstet Gynecol. 2013 May;208(5):395.e1-7. doi: 10.1016/j.ajog.2013.02.006. Epub 2013 Mar 8.
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• [4] Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas.Eur J Endocrinol. 2013 Sep 12;169(4):391-400. doi: 10.1530/EJE-13-0134. Print 2013 Oct.
• [5] Loss of expression of ZAC/PLAGL1 in diffuse large B-cell lymphoma is independent of promoter hypermethylation.Genes Chromosomes Cancer. 2010 May;49(5):480-6. doi: 10.1002/gcc.20758.
• [6] The candidate tumor suppressor gene ZAC is involved in keratinocyte differentiation and its expression is lost in basal cell carcinomas.Mol Cancer Res. 2005 Sep;3(9):483-92. doi: 10.1158/1541-7786.MCR-05-0019.
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• [10] Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus.J Biol Chem. 2001 Jun 1;276(22):18653-6. doi: 10.1074/jbc.C100095200. Epub 2001 Apr 10.
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• [29] A Novel Mutation of Aryl Hydrocarbon Receptor Interacting Protein Gene Associated with Familial Isolated Pituitary Adenoma Mediates Tumor Invasion and Growth Hormone Hypersecretion.World Neurosurg. 2019 Mar;123:e45-e59. doi: 10.1016/j.wneu.2018.11.021. Epub 2018 Nov 15.
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• [31] Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort.Epigenetics. 2014 Mar;9(3):338-45. doi: 10.4161/epi.27387. Epub 2013 Dec 6.
• [32] 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.
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