Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJCIQR2)

• DOT Name: Lysine-specific demethylase PHF2 (PHF2)
• Synonyms: EC 1.14.11.-; GRC5; PHD finger protein 2
• Gene Name: PHF2
• Related Disease:
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Hepatocellular carcinoma
  Neurodevelopmental disorder
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Head-neck squamous cell carcinoma
  Major depressive disorder
  Mood disorder
  Neoplasm
  Obesity
  Stomach cancer
  Clear cell renal carcinoma
  Childhood kidney Wilms tumor
  Wilms tumor
• UniProt ID: PHF2_HUMAN
• PDB ID: 3KQI; 3PTR; 3PU3; 3PU8; 3PUA; 3PUS; 7M10; 8F8Y; 8F8Z
• EC Number: 1.14.11.-
• Pfam ID: PF17811 ; PF02373 ; PF00628
• Sequence:
  MATVPVYCVCRLPYDVTRFMIECDACKDWFHGSCVGVEEEEAPDIDIYHCPNCEKTHGKS
  TLKKKRTWHKHGPGQAPDVKPVQNGSQLFIKELRSRTFPSAEDVVARVPGSQLTLGYMEE
  HGFTEPILVPKKDGLGLAVPAPTFYVSDVENYVGPERSVDVTDVTKQKDCKMKLKEFVDY
  YYSTNRKRVLNVTNLEFSDTRMSSFVEPPDIVKKLSWVENYWPDDALLAKPKVTKYCLIC
  VKDSYTDFHIDSGGASAWYHVLKGEKTFYLIRPASANISLYERWRSASNHSEMFFADQVD
  KCYKCIVKQGQTLFIPSGWIYATLTPVDCLAFAGHFLHSLSVEMQMRAYEVERRLKLGSL
  TQFPNFETACWYMGKHLLEAFKGSHKSGKQLPPHLVQGAKILNGAFRSWTKKQALAEHED
  ELPEHFKPSQLIKDLAKEIRLSENASKAVRPEVNTVASSDEVCDGDREKEEPPSPIEATP
  PQSLLEKVSKKKTPKTVKMPKPSKIPKPPKPPKPPRPPKTLKLKDGGKKKGKKSRESASP
  TIPNLDLLEAHTKEALTKMEPPKKGKATKSVLSVPNKDVVHMQNDVERLEIREQTKSKSE
  AKWKYKNSKPDSLLKMEEEQKLEKSPLAGNKDNKFSFSFSNKKLLGSKALRPPTSPGVFG
  ALQNFKEDKPKPVRDEYEYVSDDGELKIDEFPIRRKKNAPKRDLSFLLDKKAVLPTPVTK
  PKLDSAAYKSDDSSDEGSLHIDTDTKPGRNARVKKESGSSAAGILDLLQASEEVGALEYN
  PSSQPPASPSTQEAIQGMLSMANLQASDSCLQTTWGAGQAKGSSLAAHGARKNGGGSGKS
  AGKRLLKRAAKNSVDLDDYEEEQDHLDACFKDSDYVYPSLESDEDNPIFKSRSKKRKGSD
  DAPYSPTARVGPSVPRQDRPVREGTRVASIETGLAAAAAKLSQQEEQKSKKKKSAKRKLT
  PNTTSPSTSTSISAGTTSTSTTPASTTPASTTPASTSTASSQASQEGSSPEPPPESHSSS
  LADHEYTAAGTFTGAQAGRTSQPMAPGVFLTQRRPSASSPNNNTAAKGKRTKKGMATAKQ
  RLGKILKIHRNGKLLL
• Function: Lysine demethylase that demethylates both histones and non-histone proteins. Enzymatically inactive by itself, and becomes active following phosphorylation by PKA: forms a complex with ARID5B and mediates demethylation of methylated ARID5B. Demethylation of ARID5B leads to target the PHF2-ARID5B complex to target promoters, where PHF2 mediates demethylation of dimethylated 'Lys-9' of histone H3 (H3K9me2), followed by transcription activation of target genes. The PHF2-ARID5B complex acts as a coactivator of HNF4A in liver. PHF2 is recruited to trimethylated 'Lys-4' of histone H3 (H3K4me3) at rDNA promoters and promotes expression of rDNA. Involved in the activation of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages by catalyzing the demethylation of trimethylated histone H4 lysine 20 (H4K20me3) at the gene promoters.
• Tissue Specificity: Widely expressed, including in liver (at protein level).
• Reactome Pathway: HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:G66-32922-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Definitive	Altered Expression	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[2]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[9]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[10]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[12]
Wilms tumor	DISB6T16	Limited	Biomarker	[12]

5 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 Lysine-specific demethylase PHF2 (PHF2).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysine-specific demethylase PHF2 (PHF2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine-specific demethylase PHF2 (PHF2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lysine-specific demethylase PHF2 (PHF2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysine-specific demethylase PHF2 (PHF2).	[19]

3 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 Lysine-specific demethylase PHF2 (PHF2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Lysine-specific demethylase PHF2 (PHF2).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Lysine-specific demethylase PHF2 (PHF2).	[17]

References

• [1] Plant homeodomain finger protein 2 as a novel IKAROS target in acute lymphoblastic leukemia.Epigenomics. 2018 Jan;10(1):59-69. doi: 10.2217/epi-2017-0092. Epub 2017 Oct 10.
• [2] MiR-221 Promotes Hepatocellular Carcinoma Cells Migration via Targeting PHF2.Biomed Res Int. 2019 May 12;2019:4371405. doi: 10.1155/2019/4371405. eCollection 2019.
• [3] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [4] Histone Demethylase Gene PHF2 Is Mutated in Gastric and Colorectal Cancers.Pathol Oncol Res. 2017 Jul;23(3):471-476. doi: 10.1007/s12253-016-0130-1. Epub 2016 Oct 15.
• [5] Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma.Mol Cancer. 2008 Nov 6;7:84. doi: 10.1186/1476-4598-7-84.
• [6] Overexpression of Jumonji AT-rich interactive domain 1B and PHD finger protein 2 is involved in the progression of esophageal squamous cell carcinoma.Acta Histochem. 2013 Jan;115(1):56-62. doi: 10.1016/j.acthis.2012.04.001. Epub 2012 Apr 23.
• [7] PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer.Oncogene. 2015 May 28;34(22):2897-909. doi: 10.1038/onc.2014.219. Epub 2014 Jul 21.
• [8] Inactivation of 9q22.3 tumor suppressor genes predict outcome for patients with head and neck squamous cell carcinoma.Anticancer Res. 2013 Mar;33(3):1215-20.
• [9] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [10] The prognostic significance of nuclear expression of PHF2 and C/EBP in clear cell renal cell carcinoma with consideration of adipogenic metabolic evolution.Oncotarget. 2017 Aug 4;9(1):142-151. doi: 10.18632/oncotarget.19949. eCollection 2018 Jan 2.
• [11] Epigenetic regulation of adipogenesis by PHF2 histone demethylase.Diabetes. 2013 May;62(5):1426-34. doi: 10.2337/db12-0628. Epub 2012 Dec 28.
• [12] GRC5 and NMD3 function in translational control of gene expression and interact genetically.Curr Genet. 1999 Jan;34(6):419-29. doi: 10.1007/s002940050416.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [16] 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.
• [17] 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.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] 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.