Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV2DQDD)

• DOT Name: Core histone macro-H2A.1 (MACROH2A1)
• Synonyms: Histone macroH2A1; mH2A1; Histone H2A.y; H2A/y; Medulloblastoma antigen MU-MB-50.205
• Gene Name: MACROH2A1
• Related Disease:
  Acute myelogenous leukaemia
  Autism
  Bladder cancer
  Colon cancer
  Colon carcinoma
  Fatty liver disease
  Gastric cancer
  Hepatocellular carcinoma
  Huntington disease
  Liver cirrhosis
  Lysosomal lipid storage disorder
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Lupus
  Systemic lupus erythematosus
  Brachydactyly-elbow wrist dysplasia syndrome
  Breast cancer
  Breast carcinoma
• UniProt ID: H2AY_HUMAN
• PDB ID: 1U35; 1ZR3; 1ZR5; 2F8N; 2FXK; 3HQH; 3HSV; 3IID; 3IIF; 3IVB; 5IIT; 5LNC; 7D3Y
• Pfam ID: PF00125 ; PF16211 ; PF01661
• Sequence:
  MSSRGGKKKSTKTSRSAKAGVIFPVGRMLRYIKKGHPKYRIGVGAPVYMAAVLEYLTAEI
  LELAGNAARDNKKGRVTPRHILLAVANDEELNQLLKGVTIASGGVLPNIHPELLAKKRGS
  KGKLEAIITPPPAKKAKSPSQKKPVSKKAGGKKGARKSKKKQGEVSKAASADSTTEGTPA
  DGFTVLSTKSLFLGQKLQVVQADIASIDSDAVVHPTNTDFYIGGEVGNTLEKKGGKEFVE
  AVLELRKKNGPLEVAGAAVSAGHGLPAKFVIHCNSPVWGADKCEELLEKTVKNCLALADD
  KKLKSIAFPSIGSGRNGFPKQTAAQLILKAISSYFVSTMSSSIKTVYFVLFDSESIGIYV
  QEMAKLDAN
• Function: Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription. 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. Involved in stable X chromosome inactivation. Inhibits the binding of transcription factors, including NF-kappa-B, and interferes with the activity of remodeling SWI/SNF complexes. Inhibits histone acetylation by EP300 and recruits class I HDACs, which induces a hypoacetylated state of chromatin ; [Isoform 1]: Isoform that specifically binds poly-ADP-ribose and O-acetyl-ADP-ribose and plays a key role in NAD(+) metabolism. Able to bind to the ends of poly-ADP-ribose chains created by PARP1 and cap them. This prevents PARP1 from further addition of ADP-ribose and thus limits the consumption of nuclear NAD(+), allowing the cell to maintain proper NAD(+) levels in both the nucleus and the mitochondria to promote proper mitochondrial respiration. Increases the expression of genes involved in redox metabolism, including SOD3 ; [Isoform 2]: In contrast to isoform 1, does not bind poly-ADP-ribose. Represses SOD3 gene expression.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Necroptosis (hsa04217)
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Systemic lupus erythematosus (hsa05322)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[9]
Lysosomal lipid storage disorder	DISXQRTX	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[11]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Lupus	DISOKJWA	moderate	Genetic Variation	[14]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[14]
Brachydactyly-elbow wrist dysplasia syndrome	DIS9TZPZ	Supportive	Autosomal dominant	[15]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[16]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[16]

6 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 Core histone macro-H2A.1 (MACROH2A1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Core histone macro-H2A.1 (MACROH2A1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Core histone macro-H2A.1 (MACROH2A1).	[26]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Core histone macro-H2A.1 (MACROH2A1).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Core histone macro-H2A.1 (MACROH2A1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Core histone macro-H2A.1 (MACROH2A1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Core histone macro-H2A.1 (MACROH2A1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Core histone macro-H2A.1 (MACROH2A1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Core histone macro-H2A.1 (MACROH2A1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Core histone macro-H2A.1 (MACROH2A1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Core histone macro-H2A.1 (MACROH2A1).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Core histone macro-H2A.1 (MACROH2A1).	[33]

References

• [1] H2AFY is a novel fusion partner of MECOM in acute myeloid leukemia.Cancer Genet. 2018 Apr;222-223:9-12. doi: 10.1016/j.cancergen.2018.01.004. Epub 2018 Feb 17.
• [2] Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis.BMC Med Genet. 2007 Dec 6;8:74. doi: 10.1186/1471-2350-8-74.
• [3] MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B.Oncogene. 2016 Mar 10;35(10):1292-301. doi: 10.1038/onc.2015.187. Epub 2015 Jun 1.
• [4] Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer.Am J Pathol. 2012 Jun;180(6):2516-26. doi: 10.1016/j.ajpath.2012.02.027. Epub 2012 Apr 27.
• [5] Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma.PLoS One. 2013;8(1):e54458. doi: 10.1371/journal.pone.0054458. Epub 2013 Jan 23.
• [6] QKI5-mediated alternative splicing of the histone variant macroH2A1 regulates gastric carcinogenesis.Oncotarget. 2016 May 31;7(22):32821-34. doi: 10.18632/oncotarget.8739.
• [7] Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma.Hepatology. 2018 Feb;67(2):636-650. doi: 10.1002/hep.29519. Epub 2018 Jan 2.
• [8] Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse.Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17141-6. doi: 10.1073/pnas.1104409108. Epub 2011 Oct 3.
• [9] DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression.Cancer Res. 2016 Feb 1;76(3):594-606. doi: 10.1158/0008-5472.CAN-15-1336. Epub 2016 Jan 15.
• [10] MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis.FASEB J. 2015 May;29(5):1676-87. doi: 10.1096/fj.14-262717. Epub 2014 Dec 19.
• [11] CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity.Nat Commun. 2019 Sep 5;10(1):4013. doi: 10.1038/s41467-019-12001-2.
• [12] Histone variant MacroH2A1 is downregulated in prostate cancer and influences malignant cell phenotype.Cancer Cell Int. 2019 Apr 29;19:112. doi: 10.1186/s12935-019-0835-9. eCollection 2019.
• [13] Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells.Epigenetics. 2018;13(8):829-845. doi: 10.1080/15592294.2018.1514239. Epub 2018 Sep 29.
• [14] The Sgp3 locus derived from the 129 strain is responsible for enhanced endogenous retroviral expression in macroH2A1-deficient mice.J Autoimmun. 2010 Dec;35(4):398-403. doi: 10.1016/j.jaut.2010.08.003. Epub 2010 Sep 15.
• [15] H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome. J Med Genet. 2019 Apr;56(4):246-251. doi: 10.1136/jmedgenet-2018-105793. Epub 2019 Feb 2.
• [16] Increased macroH2A1.1 expression correlates with poor survival of triple-negative breast cancer patients.PLoS One. 2014 Jun 9;9(6):e98930. doi: 10.1371/journal.pone.0098930. eCollection 2014.
• [17] 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.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [21] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [22] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [23] 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.
• [24] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [25] PARP-1 modulates the expression of miR-223 through histone acetylation to involve in the hydroquinone-induced carcinogenesis of TK6 cells. J Biochem Mol Toxicol. 2022 Sep;36(9):e23142. doi: 10.1002/jbt.23142. Epub 2022 Jun 14.
• [26] 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.
• [27] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] 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.
• [30] 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.
• [31] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.