Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY6ITYF)

• DOT Name: Histone H3.1t (H3-4)
• Synonyms: H3/t; H3t; H3/g; Histone H3.4
• Gene Name: H3-4
• Related Disease:
  Azoospermia
  Endometriosis
  Inflammatory breast cancer
  Intellectual disability
  Neoplasm
  Non-small-cell lung cancer
  Pneumoconiosis
  Prostate neoplasm
  Pulmonary fibrosis
  Lung cancer
  Lung carcinoma
  Advanced cancer
• UniProt ID: H31T_HUMAN
• PDB ID: 2V1D; 2YBP; 2YBS; 3A6N; 3T6R; 4V2V; 4V2W; 6OIE; 6WAT; 6WAU
• Pfam ID: PF00125
• Sequence:
  MARTKQTARKSTGGKAPRKQLATKVARKSAPATGGVKKPHRYRPGTVALREIRRYQKSTE
  LLIRKLPFQRLMREIAQDFKTDLRFQSSAVMALQEACESYLVGLFEDTNLCVIHAKRVTI
  MPKDIQLARRIRGERA
• Function: Core component of nucleosome. 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.
• Tissue Specificity: Expressed in testicular cells.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Shigellosis (hsa05131)
  Transcriptio.l misregulation in cancer (hsa05202)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)
  Cleavage of the damaged purine (R-HSA-110331)
  Meiotic synapsis (R-HSA-1221632)
  Packaging Of Telomere Ends (R-HSA-171306)
  Formation of the beta-catenin (R-HSA-201722)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Meiotic recombination (R-HSA-912446)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Azoospermia	DIS94181	Strong	Biomarker	[1]
Endometriosis	DISX1AG8	Strong	Biomarker	[2]
Inflammatory breast cancer	DIS3QRWA	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[6]
Pneumoconiosis	DISSJLBN	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[8]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Disputed	Biomarker	[10]
Lung carcinoma	DISTR26C	Disputed	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Histone H3.1t (H3-4).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the acetylation of Histone H3.1t (H3-4).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Histone H3.1t (H3-4).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the acetylation of Histone H3.1t (H3-4).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the acetylation of Histone H3.1t (H3-4).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the methylation of Histone H3.1t (H3-4).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat increases the acetylation of Histone H3.1t (H3-4).	[19]
Romidepsin	DMT5GNL	Approved	Romidepsin increases the acetylation of Histone H3.1t (H3-4).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the acetylation of Histone H3.1t (H3-4).	[22]
MGCD-0103	DM726HX	Phase 2	MGCD-0103 increases the acetylation of Histone H3.1t (H3-4).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the methylation of Histone H3.1t (H3-4).	[18]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the acetylation of Histone H3.1t (H3-4).	[26]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the methylation of Histone H3.1t (H3-4).	[27]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the acetylation of Histone H3.1t (H3-4).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone H3.1t (H3-4).	[14]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Histone H3.1t (H3-4).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Histone H3.1t (H3-4).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone H3.1t (H3-4).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone H3.1t (H3-4).	[25]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Histone H3.1t (H3-4).	[29]

References

• [1] Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis.Cell Rep. 2017 Jan 17;18(3):593-600. doi: 10.1016/j.celrep.2016.12.065.
• [2] Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications.Reprod Sci. 2014 Mar;21(3):305-18. doi: 10.1177/1933719113497267. Epub 2013 Jul 30.
• [3] Overexpression of caveolin-1 in inflammatory breast cancer cells enables IBC-specific gene delivery and prodrug conversion using histone-targeted polyplexes.Biotechnol Bioeng. 2016 Dec;113(12):2686-2697. doi: 10.1002/bit.26022. Epub 2016 Jun 9.
• [4] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [5] Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials.Curr Treat Options Neurol. 2019 Jul 10;21(8):37. doi: 10.1007/s11940-019-0577-y.
• [6] G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells.Cell Death Dis. 2017 Apr 6;8(4):e2726. doi: 10.1038/cddis.2017.65.
• [7] Pathway analysis for a genome-wide association study of pneumoconiosis.Toxicol Lett. 2015 Jan 5;232(1):284-92. doi: 10.1016/j.toxlet.2014.10.028. Epub 2014 Nov 4.
• [8] JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer.Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19226-31. doi: 10.1073/pnas.0700735104. Epub 2007 Nov 28.
• [9] Effects of dynamic changes in histone acetylation and deacetylase activity on pulmonary fibrosis.Int Immunopharmacol. 2017 Nov;52:272-280. doi: 10.1016/j.intimp.2017.09.020. Epub 2017 Sep 27.
• [10] Triptolide inhibits Wnt signaling in NSCLC through upregulation of multiple Wnt inhibitory factors via epigenetic modifications to Histone H3.Int J Cancer. 2018 Nov 15;143(10):2470-2478. doi: 10.1002/ijc.31756. Epub 2018 Sep 19.
• [11] A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC.Sci Rep. 2017 May 15;7(1):1900. doi: 10.1038/s41598-017-01964-1.
• [12] 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.
• [13] Down-regulation of the tumor suppressor gene retinoic acid receptor beta2 through the phosphoinositide 3-kinase/Akt signaling pathway. Mol Endocrinol. 2006 Sep;20(9):2109-21. doi: 10.1210/me.2005-0321. Epub 2006 Apr 13.
• [14] 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.
• [15] Inhalable metal-rich air particles and histone H3K4 dimethylation and H3K9 acetylation in a cross-sectional study of steel workers. Environ Health Perspect. 2011 Jul;119(7):964-9. doi: 10.1289/ehp.1002955. Epub 2011 Mar 8.
• [16] Quercetin augments TRAIL-induced apoptotic death: involvement of the ERK signal transduction pathway. Biochem Pharmacol. 2008 May 15;75(10):1946-58. doi: 10.1016/j.bcp.2008.02.016. Epub 2008 Mar 10.
• [17] Combined effects of retinoic acid and histone deacetylase inhibitors on human neuroblastoma SH-SY5Y cells. Mol Cancer Ther. 2007 Apr;6(4):1425-32. doi: 10.1158/1535-7163.MCT-06-0623.
• [18] Epigenetic silencing of maspin expression occurs early in the conversion of keratocytes to fibroblasts. Exp Eye Res. 2008 Apr;86(4):586-600. doi: 10.1016/j.exer.2008.01.003. Epub 2008 Jan 12.
• [19] A systematic assessment of radiation dose enhancement by 5-Aza-2'-deoxycytidine and histone deacetylase inhibitors in head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):904-12. doi: 10.1016/j.ijrobp.2008.10.032.
• [20] Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol. 2005 Aug;174(2):747-52. doi: 10.1097/01.ju.0000164723.20555.e6.
• [21] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [22] Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3. Arch Toxicol. 2022 Jan;96(1):177-193. doi: 10.1007/s00204-021-03174-1. Epub 2021 Oct 19.
• [23] BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis. 2009 Apr;30(4):662-70. doi: 10.1093/carcin/bgp042. Epub 2009 Feb 12.
• [24] Poly(ADP-ribose) glycohydrolase silencing-mediated H2B expression inhibits benzo(a)pyrene-induced carcinogenesis. Environ Toxicol. 2021 Mar;36(3):291-297. doi: 10.1002/tox.23034. Epub 2020 Oct 12.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] Alterations of histone modifications and transgene silencing by nickel chloride. Carcinogenesis. 2006 Jul;27(7):1481-8. doi: 10.1093/carcin/bgl004. Epub 2006 Mar 7.
• [27] Carcinogen-induced histone alteration in normal human mammary epithelial cells. Carcinogenesis. 2007 Oct;28(10):2184-92. doi: 10.1093/carcin/bgm100. Epub 2007 Apr 29.
• [28] Valproate potentiates androgen biosynthesis in human ovarian theca cells. Endocrinology. 2004 Feb;145(2):799-808.
• [29] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.