Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIY1J5L)

• DOT Name: Polycomb group RING finger protein 2 (PCGF2)
• Synonyms: DNA-binding protein Mel-18; RING finger protein 110; Zinc finger protein 144
• Gene Name: PCGF2
• Related Disease:
  Esophageal squamous cell carcinoma
  Adenoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Cardiac failure
  Colitis
  Congestive heart failure
  Esophageal cancer
  Gastric cancer
  Intellectual disability
  Medulloblastoma
  Metastatic malignant neoplasm
  Neoplasm of esophagus
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Triple negative breast cancer
  Turnpenny-fry syndrome
  Her2-receptor negative breast cancer
  HER2/NEU overexpressing breast cancer
  Salla disease
  Acute myelogenous leukaemia
  Melanoma
  Squamous cell carcinoma
• UniProt ID: PCGF2_HUMAN
• Pfam ID: PF16207 ; PF13923
• Sequence:
  MHRTTRIKITELNPHLMCALCGGYFIDATTIVECLHSFCKTCIVRYLETNKYCPMCDVQV
  HKTRPLLSIRSDKTLQDIVYKLVPGLFKDEMKRRRDFYAAYPLTEVPNGSNEDRGEVLEQ
  EKGALSDDEIVSLSIEFYEGARDRDEKKGPLENGDGDKEKTGVRFLRCPAAMTVMHLAKF
  LRNKMDVPSKYKVEVLYEDEPLKEYYTLMDIAYIYPWRRNGPLPLKYRVQPACKRLTLAT
  VPTPSEGTNTSGASECESVSDKAPSPATLPATSSSLPSPATPSHGSPSSHGPPATHPTSP
  TPPSTASGATTAANGGSLNCLQTPSSTSRGRKMTVNGAPVPPLT
• Function: Transcriptional repressor. Binds specifically to the DNA sequence 5'-GACTNGACT-3'. Has tumor suppressor activity. May play a role in control of cell proliferation and/or neural cell development. Regulates proliferation of early T progenitor cells by maintaining expression of HES1. Also plays a role in antero-posterior specification of the axial skeleton and negative regulation of the self-renewal activity of hematopoietic stem cells. Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity.
• Tissue Specificity: Detected in all tissues examined with high expression found in placenta lung and kidney and low expression, in liver, pancreas and skeletal muscle.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA methylation proteins (R-HSA-4655427)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[1]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[10]
Turnpenny-fry syndrome	DISYZYW0	Strong	Autosomal dominant	[11]
Her2-receptor negative breast cancer	DISS605N	moderate	Biomarker	[3]
HER2/NEU overexpressing breast cancer	DISYKID5	moderate	Biomarker	[3]
Salla disease	DISA4PBW	moderate	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[12]
Melanoma	DIS1RRCY	Limited	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[13]

1 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 Polycomb group RING finger protein 2 (PCGF2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polycomb group RING finger protein 2 (PCGF2).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Polycomb group RING finger protein 2 (PCGF2).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Polycomb group RING finger protein 2 (PCGF2).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Polycomb group RING finger protein 2 (PCGF2).	[18]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Polycomb group RING finger protein 2 (PCGF2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Polycomb group RING finger protein 2 (PCGF2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Polycomb group RING finger protein 2 (PCGF2).	[17]

References

• [1] Co-inhibition of BMI1 and Mel18 enhances chemosensitivity of esophageal squamous cell carcinoma in vitro and in vivo.Oncol Lett. 2019 Jun;17(6):5012-5022. doi: 10.3892/ol.2019.10160. Epub 2019 Mar 19.
• [2] BMI1 and MEL18 Promote Colitis-Associated Cancer inMiceviaREG3B and STAT3.Gastroenterology. 2017 Dec;153(6):1607-1620. doi: 10.1053/j.gastro.2017.07.044. Epub 2017 Aug 3.
• [3] Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer.J Natl Cancer Inst. 2019 Jun 1;111(6):609-619. doi: 10.1093/jnci/djy151.
• [4] Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy.Int J Cardiol. 2018 Apr 15;257:283-290. doi: 10.1016/j.ijcard.2017.10.102. Epub 2017 Nov 10.
• [5] Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer.Oncotarget. 2016 Sep 27;7(39):63352-63361. doi: 10.18632/oncotarget.11221.
• [6] Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features.Am J Hum Genet. 2018 Dec 6;103(6):1054-1055. doi: 10.1016/j.ajhg.2018.11.009.
• [7] Polycomb genes expression as a predictor of poor clinical outcome in children with medulloblastoma.Childs Nerv Syst. 2011 Jan;27(1):79-86. doi: 10.1007/s00381-010-1260-5. Epub 2010 Aug 18.
• [8] Analysis of Mel-18 expression in prostate cancer tissues and correlation with clinicopathologic features.Urol Oncol. 2011 May-Jun;29(3):244-51. doi: 10.1016/j.urolonc.2009.02.004. Epub 2009 Apr 22.
• [9] PCGF2 negatively regulates arsenic trioxide-induced PML-RARA protein degradation via UBE2I inhibition in NB4 cells.Biochim Biophys Acta. 2016 Jul;1863(7 Pt A):1499-509. doi: 10.1016/j.bbamcr.2016.03.019. Epub 2016 Mar 24.
• [10] MEL-18 loss mediates estrogen receptor- downregulation and hormone independence.J Clin Invest. 2015 May;125(5):1801-14. doi: 10.1172/JCI73743. Epub 2015 Mar 30.
• [11] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [12] Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia.Eur J Haematol. 2008 Aug;81(2):112-22. doi: 10.1111/j.1600-0609.2008.01083.x. Epub 2008 Jun 28.
• [13] Prognostic Significance of BMI-1 But Not MEL-18 Expression in Pulmonary Squamous Cell Carcinoma.Anticancer Res. 2017 Apr;37(4):1923-1929. doi: 10.21873/anticanres.11531.
• [14] 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.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] 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.