Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW2PSIR)

• DOT Name: PHD finger protein 1 (PHF1)
• Synonyms: Protein PHF1; hPHF1; Polycomb-like protein 1; hPCl1
• Gene Name: PHF1
• Related Disease:
  Fanconi anemia complementation group A
  Fanconi's anemia
  Friedreich ataxia 1
  Pick disease
  Advanced cancer
  Frontotemporal dementia
  Alzheimer disease
  Parkinson disease
  Parkinsonian disorder
• UniProt ID: PHF1_HUMAN
• PDB ID: 2E5P; 2M0O; 4HCZ; 5XFN; 5XFO; 5XFP; 6WAT; 6WAV; 7LKY
• Pfam ID: PF14061 ; PF00628 ; PF18104
• Sequence:
  MAQPPRLSRSGASSLWDPASPAPTSGPRPRLWEGQDVLARWTDGLLYLGTIKKVDSAREV
  CLVQFEDDSQFLVLWKDISPAALPGEELLCCVCRSETVVPGNRLVSCEKCRHAYHQDCHV
  PRAPAPGEGEGTSWVCRQCVFAIATKRGGALKKGPYARAMLGMKLSLPYGLKGLDWDAGH
  LSNRQQSYCYCGGPGEWNLKMLQCRSCLQWFHEACTQCLSKPLLYGDRFYEFECCVCRGG
  PEKVRRLQLRWVDVAHLVLYHLSVCCKKKYFDFDREILPFTSENWDSLLLGELSDTPKGE
  RSSRLLSALNSHKDRFISGREIKKRKCLFGLHARMPPPVEPPTGDGALTSFPSGQGPGGG
  VSRPLGKRRRPEPEPLRRRQKGKVEELGPPSAVRNQPEPQEQRERAHLQRALQASVSPPS
  PSPNQSYQGSSGYNFRPTDARCLPSSPIRMFASFHPSASTAGTSGDSGPPDRSPLELHIG
  FPTDIPKSAPHSMTASSSSVSSPSPGLPRRSAPPSPLCRSLSPGTGGGVRGGVGYLSRGD
  PVRVLARRVRPDGSVQYLVEWGGGGIF
• Function: Polycomb group (PcG) that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex. Involved in DNA damage response and is recruited at double-strand breaks (DSBs). Acts by binding to H3K36me3, a mark for transcriptional activation, and recruiting the PRC2 complex: it is however unclear whether recruitment of the PRC2 complex to H3K36me3 leads to enhance or inhibit H3K27me3 methylation mediated by the PRC2 complex. According to some reports, PRC2 recruitment by PHF1 promotes H3K27me3 and subsequent gene silencing by inducing spreading of PRC2 and H3K27me3 into H3K36me3 loci. According to another report, PHF1 recruits the PRC2 complex at double-strand breaks (DSBs) and inhibits the activity of PRC2. Regulates p53/TP53 stability and prolonges its turnover: may act by specifically binding to a methylated from of p53/TP53.
• Tissue Specificity: Highest levels in heart, skeletal muscle, and pancreas, lower levels in brain, placenta, lung, liver and kidney.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[1]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[1]
Friedreich ataxia 1	DIS285GE	Strong	Genetic Variation	[1]
Pick disease	DISP6X50	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[4]
Alzheimer disease	DISF8S70	Limited	Biomarker	[5]
Parkinson disease	DISQVHKL	Limited	Biomarker	[6]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of PHD finger protein 1 (PHF1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of PHD finger protein 1 (PHF1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PHD finger protein 1 (PHF1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of PHD finger protein 1 (PHF1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of PHD finger protein 1 (PHF1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of PHD finger protein 1 (PHF1).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of PHD finger protein 1 (PHF1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of PHD finger protein 1 (PHF1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of PHD finger protein 1 (PHF1).	[17]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of PHD finger protein 1 (PHF1).	[18]
Linalool	DMGZQ5P	Investigative	Linalool decreases the expression of PHD finger protein 1 (PHF1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of PHD finger protein 1 (PHF1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of PHD finger protein 1 (PHF1).	[15]

References

• [1] A double-labeling immunohistochemical study of tau exon 10 in Alzheimer's disease, progressive supranuclear palsy and Pick's disease.Acta Neuropathol. 2000 Sep;100(3):235-44. doi: 10.1007/s004019900177.
• [2] Humanized monoclonal antibody armanezumab specific to N-terminus of pathological tau: characterization and therapeutic potency.Mol Neurodegener. 2017 May 5;12(1):33. doi: 10.1186/s13024-017-0172-1.
• [3] PHD finger protein 1 (PHF1) is a novel reader for histone H4R3 symmetric dimethylation and coordinates with PRMT5-WDR77/CRL4B complex to promote tumorigenesis.Nucleic Acids Res. 2018 Jul 27;46(13):6608-6626. doi: 10.1093/nar/gky461.
• [4] Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice.J Neurosci. 2016 Dec 7;36(49):12425-12435. doi: 10.1523/JNEUROSCI.2016-16.2016.
• [5] Tau pathology and neurochemical changes associated with memory dysfunction in an optimised murine model of global cerebral ischaemia - A potential model for vascular dementia?.Neurochem Int. 2018 Sep;118:134-144. doi: 10.1016/j.neuint.2018.04.004. Epub 2018 Apr 10.
• [6] Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.FASEB J. 2006 Nov;20(13):2302-12. doi: 10.1096/fj.06-6092com.
• [7] The neurotoxin, MPP+, induces hyperphosphorylation of Tau, in the presence of alpha-Synuclein, in SH-SY5Y neuroblastoma cells.Neurotox Res. 2006 Aug;10(1):1-10. doi: 10.1007/BF03033329.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] 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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.