Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3KJJNQ)

• DOT Name: Histone H2A.Z (H2AZ1)
• Synonyms: H2A/z
• Gene Name: H2AZ1
• Related Disease:
  Acute lymphocytic leukaemia
  Adenoma
  Autism
  Breast neoplasm
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Lung cancer
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Vascular disease
  Adult hepatocellular carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Intrahepatic cholangiocarcinoma
  Liver cancer
  Melanoma
  Metastatic malignant neoplasm
  Nervous system disease
  Neurodevelopmental disorder
  Small-cell lung cancer
  Urinary bladder cancer
• UniProt ID: H2AZ_HUMAN
• PDB ID: 1F66; 3WA9; 4CAY; 4NFT; 5B31; 5B32; 5B33; 5CHL; 5FUG; 5Z30; 6JOU; 6KO2; 7YRD; 8JHF; 8T9F; 8THU
• Pfam ID: PF00125 ; PF16211
• Sequence:
  MAGGKAGKDSGKAKTKAVSRSQRAGLQFPVGRIHRHLKSRTTSHGRVGATAAVYSAAILE
  YLTAEVLELAGNASKDLKVKRITPRHLQLAIRGDEELDSLIKATIAGGGVIPHIHKSLIG
  KKGQQKTV
• Function: Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Necroptosis (hsa04217)
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway: Amyloid fiber formation (R-HSA-977225)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[7]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[8]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Vascular disease	DISVS67S	Strong	Biomarker	[13]
Adult hepatocellular carcinoma	DIS6ZPAI	Limited	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[14]
Breast cancer	DIS7DPX1	Limited	Biomarker	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Limited	Biomarker	[6]
Liver cancer	DISDE4BI	Limited	Biomarker	[6]
Melanoma	DIS1RRCY	Limited	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[6]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[17]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[17]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[18]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Histone H2A.Z (H2AZ1).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Histone H2A.Z (H2AZ1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone H2A.Z (H2AZ1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone H2A.Z (H2AZ1).	[22]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Histone H2A.Z (H2AZ1).	[23]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Histone H2A.Z (H2AZ1).	[24]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Histone H2A.Z (H2AZ1).	[25]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide increases the expression of Histone H2A.Z (H2AZ1).	[26]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Histone H2A.Z (H2AZ1).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Histone H2A.Z (H2AZ1).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Histone H2A.Z (H2AZ1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone H2A.Z (H2AZ1).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Histone H2A.Z (H2AZ1).	[30]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Histone H2A.Z (H2AZ1).	[31]

References

• [1] Significance of CASP8AP2 and H2AFZ expression in survival and risk of relapse in children with acute lymphoblastic leukemia.Leuk Lymphoma. 2014 Oct;55(10):2305-11. doi: 10.3109/10428194.2013.878458. Epub 2014 Feb 24.
• [2] Molecular mechanisms underlying the tumorigenesis of colorectal adenomas: correlation to activated K-ras oncogene.Oncol Rep. 2006 Dec;16(6):1245-52.
• [3] UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons.Epigenetics. 2017;12(11):982-990. doi: 10.1080/15592294.2017.1376151. Epub 2017 Nov 6.
• [4] Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.Mol Syst Biol. 2008;4:188. doi: 10.1038/msb.2008.25. Epub 2008 Apr 15.
• [5] Circulating cell-free nucleosomes as biomarkers for early detection of colorectal cancer.Oncotarget. 2017 Oct 20;9(12):10247-10258. doi: 10.18632/oncotarget.21908. eCollection 2018 Feb 13.
• [6] H2A.Z regulates tumorigenesis, metastasis and sensitivity to cisplatin in intrahepatic cholangiocarcinoma.Int J Oncol. 2018 Apr;52(4):1235-1245. doi: 10.3892/ijo.2018.4292. Epub 2018 Feb 28.
• [7] Possible role of intragenic DNA hypermethylation in gene silencing of the tumor suppressor gene NR4A3 in acute myeloid leukemia.Leuk Res. 2016 Nov;50:85-94. doi: 10.1016/j.leukres.2016.09.018. Epub 2016 Sep 26.
• [8] Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis.J Clin Invest. 2013 Mar;123(3):1241-61. doi: 10.1172/JCI61271. Epub 2013 Feb 15.
• [9] Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer.Genome Res. 2012 Feb;22(2):307-21. doi: 10.1101/gr.118919.110. Epub 2011 Jul 25.
• [10] Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer.Genes Dev. 2018 Jan 1;32(1):58-69. doi: 10.1101/gad.303784.117. Epub 2018 Feb 1.
• [11] Metformin alters H2A.Z dynamics and regulates androgen dependent prostate cancer progression.Oncotarget. 2018 Dec 11;9(97):37054-37068. doi: 10.18632/oncotarget.26457. eCollection 2018 Dec 11.
• [12] Association study of H2AFZ with schizophrenia in a Japanese case-control sample.J Neural Transm (Vienna). 2015 Jun;122(6):915-23. doi: 10.1007/s00702-014-1332-x. Epub 2014 Nov 13.
• [13] Histone Variant H2A.Z Is Required for the Maintenance of Smooth Muscle Cell Identity as Revealed by Single-Cell Transcriptomics.Circulation. 2018 Nov 13;138(20):2274-2288. doi: 10.1161/CIRCULATIONAHA.117.033114.
• [14] The H2A.Z histone variant integrates Wnt signaling in intestinal epithelial homeostasis.Nat Commun. 2019 Apr 23;10(1):1827. doi: 10.1038/s41467-019-09899-z.
• [15] Significant prognostic values of differentially expressed-aberrantly methylated hub genes in breast cancer.J Cancer. 2019 Oct 21;10(26):6618-6634. doi: 10.7150/jca.33433. eCollection 2019.
• [16] Oncogenic potential of histone-variant H2A.Z.1 and its regulatory role in cell cycle and epithelial-mesenchymal transition in liver cancer.Oncotarget. 2016 Mar 8;7(10):11412-23. doi: 10.18632/oncotarget.7194.
• [17] Brain-specific deletion of histone variant H2A.z results in cortical neurogenesis defects and neurodevelopmental disorder.Nucleic Acids Res. 2018 Mar 16;46(5):2290-2307. doi: 10.1093/nar/gkx1295.
• [18] Key genes in lung cancer translational research: a meta-analysis.Pathobiology. 2010;77(2):53-63. doi: 10.1159/000278292. Epub 2010 Mar 22.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [22] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [23] Cell cycle and anti-estrogen effects synergize to regulate cell proliferation and ER target gene expression. PLoS One. 2010 Jun 8;5(6):e11011. doi: 10.1371/journal.pone.0011011.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [25] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [26] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [27] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.