Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU3FFG4)

• DOT Name: PHD finger protein 21A (PHF21A)
• Synonyms: BHC80a; BRAF35-HDAC complex protein BHC80
• Gene Name: PHF21A
• Related Disease:
  Complex neurodevelopmental disorder
  Aniridia
  Autism spectrum disorder
  Epithelial ovarian cancer
  Glioma
  Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
  Intellectual disability
  Neoplasm
  Peeling skin syndrome 1
  Pervasive developmental disorder
  Potocki-Shaffer syndrome
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Syndactyly
  Systemic sclerosis
  Venous thromboembolism
  Neurodevelopmental disorder
  Osteoarthritis
• UniProt ID: PF21A_HUMAN
• PDB ID: 2PUY; 2YQL
• Pfam ID: PF00628
• Sequence:
  MELQTLQEALKVEIQVHQKLVAQMKQDPQNADLKKQLHELQAKITALSEKQKRVVEQLRK
  NLIVKQEQPDKFQIQPLPQSENKLQTAQQQPLQQLQQQQQYHHHHAQQSAAASPNLTASQ
  KTVTTASMITTKTLPLVLKAATATMPASVVGQRPTIAMVTAINSQKAVLSTDVQNTPVNL
  QTSSKVTGPGAEAVQIVAKNTVTLVQATPPQPIKVPQFIPPPRLTPRPNFLPQVRPKPVA
  QNNIPIAPAPPPMLAAPQLIQRPVMLTKFTPTTLPTSQNSIHPVRVVNGQTATIAKTFPM
  AQLTSIVIATPGTRLAGPQTVQLSKPSLEKQTVKSHTETDEKQTESRTITPPAAPKPKRE
  ENPQKLAFMVSLGLVTHDHLEEIQSKRQERKRRTTANPVYSGAVFEPERKKSAVTYLNST
  MHPGTRKRGRPPKYNAVLGFGALTPTSPQSSHPDSPENEKTETTFTFPAPVQPVSLPSPT
  STDGDIHEDFCSVCRKSGQLLMCDTCSRVYHLDCLDPPLKTIPKGMWICPRCQDQMLKKE
  EAIPWPGTLAIVHSYIAYKAAKEEEKQKLLKWSSDLKQEREQLEQKVKQLSNSISKCMEM
  KNTILARQKEMHSSLEKVKQLIRLIHGIDLSKPVDSEATVGAISNGPDCTPPANAATSTP
  APSPSSQSCTANCNQGEETK
• Function: Component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it may act as a scaffold. Inhibits KDM1A-mediated demethylation of 'Lys-4' of histone H3 in vitro, suggesting a role in demethylation regulation.
• Tissue Specificity: Highly expressed in brain . Expressed at lower level in other tissues, including heart, kidney, liver, lung and skeletal muscle . Abundantly expressed in fetal brain .
• Reactome Pathway:
  Potential therapeutics for SARS (R-HSA-9679191)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Aniridia	DIS1P333	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures	DISEN8S9	Strong	Autosomal dominant	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Peeling skin syndrome 1	DIS35574	Strong	Biomarker	[3]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[3]
Potocki-Shaffer syndrome	DISKGU59	Strong	Autosomal dominant	[8]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Syndactyly	DISZK2BT	Strong	Genetic Variation	[9]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[3]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[10]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[11]
Osteoarthritis	DIS05URM	Limited	Biomarker	[12]

12 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 21A (PHF21A).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PHD finger protein 21A (PHF21A).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PHD finger protein 21A (PHF21A).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PHD finger protein 21A (PHF21A).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of PHD finger protein 21A (PHF21A).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PHD finger protein 21A (PHF21A).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of PHD finger protein 21A (PHF21A).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of PHD finger protein 21A (PHF21A).	[20]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of PHD finger protein 21A (PHF21A).	[21]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of PHD finger protein 21A (PHF21A).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of PHD finger protein 21A (PHF21A).	[23]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of PHD finger protein 21A (PHF21A).	[26]

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 affects the methylation of PHD finger protein 21A (PHF21A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of PHD finger protein 21A (PHF21A).	[25]

References

• [1] 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.
• [2] Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome.PLoS One. 2016 Apr 28;11(4):e0153757. doi: 10.1371/journal.pone.0153757. eCollection 2016.
• [3] De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies.Eur J Hum Genet. 2019 Mar;27(3):378-383. doi: 10.1038/s41431-018-0289-x. Epub 2018 Nov 28.
• [4] In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer.Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7301-E7310. doi: 10.1073/pnas.1705441114. Epub 2017 Aug 15.
• [5] The Identification of Key Genes and Pathways in Glioma by Bioinformatics Analysis.J Immunol Res. 2017;2017:1278081. doi: 10.1155/2017/1278081. Epub 2017 Dec 6.
• [6] Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. Am J Hum Genet. 2012 Jul 13;91(1):56-72. doi: 10.1016/j.ajhg.2012.05.005. Epub 2012 Jul 5.
• [7] RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression.Eur Urol. 2019 Aug;76(2):157-166. doi: 10.1016/j.eururo.2019.03.011. Epub 2019 Mar 23.
• [8] The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients. Clin Dysmorphol. 2023 Apr 1;32(2):49-54. doi: 10.1097/MCD.0000000000000455. Epub 2023 Feb 21.
• [9] Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism.Mol Autism. 2019 Oct 22;10:35. doi: 10.1186/s13229-019-0286-0. eCollection 2019.
• [10] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [11] Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders.Epigenomics. 2015;7(3):503-19. doi: 10.2217/epi.15.1.
• [12] Identification of Novel Genes in Osteoarthritic Fibroblast-Like Synoviocytes Using Next-Generation Sequencing and Bioinformatics Approaches.Int J Med Sci. 2019 Jul 21;16(8):1057-1071. doi: 10.7150/ijms.35611. eCollection 2019.
• [13] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [14] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [19] 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.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [22] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.