Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6RUCR)

• DOT Name: PHD finger protein 19 (PHF19)
• Synonyms: Polycomb-like protein 3; hPCL3
• Gene Name: PHF19
• Related Disease:
  Advanced cancer
  Epithelial ovarian cancer
  Ewing sarcoma
  Glioma
  Liver cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Asthma
  Autoimmune disease
  Immune system disorder
  Melanoma
  Plasma cell myeloma
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: PHF19_HUMAN
• PDB ID: 2E5Q; 4BD3; 6NQ3; 6WAU
• Pfam ID: PF14061 ; PF00628 ; PF18104
• Sequence:
  MENRALDPGTRDSYGATSHLPNKGALAKVKNNFKDLMSKLTEGQYVLCRWTDGLYYLGKI
  KRVSSSKQSCLVTFEDNSKYWVLWKDIQHAGVPGEEPKCNICLGKTSGPLNEILICGKCG
  LGYHQQCHIPIAGSADQPLLTPWFCRRCIFALAVRKGGALKKGAIARTLQAVKMVLSYQP
  EELEWDSPHRTNQQQCYCYCGGPGEWYLRMLQCYRCRQWFHEACTQCLNEPMMFGDRFYL
  FFCSVCNQGPEYIERLPLRWVDVVHLALYNLGVQSKKKYFDFEEILAFVNHHWELLQLGK
  LTSTPVTDRGPHLLNALNSYKSRFLCGKEIKKKKCIFRLRIRVPPNPPGKLLPDKGLLPN
  ENSASSELRKRGKSKPGLLPHEFQQQKRRVYRRKRSKFLLEDAIPSSDFTSAWSTNHHLA
  SIFDFTLDEIQSLKSASSGQTFFSDVDSTDAASTSGSASTSLSYDSRWTVGSRKRKLAAK
  AYMPLRAKRWAAELDGRCPSDSSAEGASVPERPDEGIDSHTFESISEDDSSLSHLKSSIT
  NYFGAAGRLACGEKYQVLARRVTPEGKVQYLVEWEGTTPY
• Function: Polycomb group (PcG) protein that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex, thus enhancing PRC2 H3K27me3 methylation activity. Probably involved in the transition from an active state to a repressed state in embryonic stem cells: acts by binding to H3K36me3, a mark for transcriptional activation, and recruiting H3K36me3 histone demethylases RIOX1 or KDM2B, leading to demethylation of H3K36 and recruitment of the PRC2 complex that mediates H3K27me3 methylation, followed by de novo silencing. Recruits the PRC2 complex to CpG islands and contributes to embryonic stem cell self-renewal. Also binds histone H3 dimethylated at 'Lys-36' (H3K36me2). Isoform 1 and isoform 2 inhibit transcription from an HSV-tk promoter.
• Tissue Specificity: Isoform 1 is expressed in thymus, heart, lung and kidney. Isoform 2 is predominantly expressed in placenta, skeletal muscle and kidney, whereas isoform 1 is predominantly expressed in liver and peripheral blood leukocytes. Overexpressed in many types of cancers, including colon, skin, lung, rectal, cervical, uterus, liver cancers, in cell lines derived from different stages of melanoma and in glioma cell lines.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Liver cancer	DISDE4BI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[2]
Asthma	DISW9QNS	moderate	Genetic Variation	[7]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[8]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[8]
Melanoma	DIS1RRCY	moderate	Biomarker	[9]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[6]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[10]

2 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 PHD finger protein 19 (PHF19).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of PHD finger protein 19 (PHF19).	[22]

16 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 PHD finger protein 19 (PHF19).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PHD finger protein 19 (PHF19).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of PHD finger protein 19 (PHF19).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of PHD finger protein 19 (PHF19).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of PHD finger protein 19 (PHF19).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of PHD finger protein 19 (PHF19).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of PHD finger protein 19 (PHF19).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of PHD finger protein 19 (PHF19).	[18]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of PHD finger protein 19 (PHF19).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of PHD finger protein 19 (PHF19).	[20]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of PHD finger protein 19 (PHF19).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of PHD finger protein 19 (PHF19).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of PHD finger protein 19 (PHF19).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PHD finger protein 19 (PHF19).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of PHD finger protein 19 (PHF19).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of PHD finger protein 19 (PHF19).	[26]

References

• [1] miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8(+) T cell fate.Nat Commun. 2019 May 14;10(1):2157. doi: 10.1038/s41467-019-09882-8.
• [2] miR-211 sponges lncRNA MALAT1 to suppress tumor growth and progression through inhibiting PHF19 in ovarian carcinoma.FASEB J. 2018 Jun 6:fj201800495RR. doi: 10.1096/fj.201800495RR. Online ahead of print.
• [3] EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins.Cancer Res. 2018 Aug 15;78(16):4760-4773. doi: 10.1158/0008-5472.CAN-18-0484. Epub 2018 Jun 13.
• [4] microRNA-124a suppresses PHF19 over-expression, EZH2 hyper-activation, and aberrant cell proliferation in human glioma.Biochem Biophys Res Commun. 2018 Sep 10;503(3):1610-1617. doi: 10.1016/j.bbrc.2018.07.089. Epub 2018 Aug 18.
• [5] A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers.Gene. 2004 Dec 8;343(1):69-78. doi: 10.1016/j.gene.2004.09.006.
• [6] PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation.Blood. 2019 Oct 3;134(14):1176-1189. doi: 10.1182/blood.2019000578. Epub 2019 Aug 5.
• [7] Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.Lancet. 2011 Sep 10;378(9795):1006-14. doi: 10.1016/S0140-6736(11)60874-X.
• [8] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [9] PHF19 and Akt control the switch between proliferative and invasive states in melanoma.Cell Cycle. 2012 Apr 15;11(8):1634-45. doi: 10.4161/cc.20095. Epub 2012 Apr 15.
• [10] PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/-catenin axis.Cell Death Dis. 2018 Oct 15;9(11):1049. doi: 10.1038/s41419-018-1082-z.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] 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.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [22] 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.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [24] 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.
• [25] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.