Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAN7RD9)

• DOT Name: Histone H1.5 (H1-5)
• Synonyms: Histone H1a; Histone H1b; Histone H1s-3
• Gene Name: H1-5
• Related Disease:
  Hepatitis C virus infection
  Pancreatic cancer
  Schizophrenia
• UniProt ID: H15_HUMAN
• PDB ID: 2RHI
• Pfam ID: PF00538
• Sequence:
  MSETAPAETATPAPVEKSPAKKKATKKAAGAGAAKRKATGPPVSELITKAVAASKERNGL
  SLAALKKALAAGGYDVEKNNSRIKLGLKSLVSKGTLVQTKGTGASGSFKLNKKAASGEAK
  PKAKKAGAAKAKKPAGATPKKAKKAAGAKKAVKKTPKKAKKPAAAGVKKVAKSPKKAKAA
  AKPKKATKSPAKPKAVKPKAAKPKAAKPKAAKPKAAKAKKAAAKKK
• Function: Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation.
• Tissue Specificity: Ubiquitous. Expressed in the majority of the cell lines tested and in testis.
• Reactome Pathway:
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)
  Apoptosis induced DNA fragmentation (R-HSA-140342)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[1]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone H1.5 (H1-5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone H1.5 (H1-5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone H1.5 (H1-5).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone H1.5 (H1-5).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone H1.5 (H1-5).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Histone H1.5 (H1-5).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Histone H1.5 (H1-5).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Histone H1.5 (H1-5).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Histone H1.5 (H1-5).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Histone H1.5 (H1-5).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Histone H1.5 (H1-5).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histone H1.5 (H1-5).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Histone H1.5 (H1-5).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Histone H1.5 (H1-5).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Histone H1.5 (H1-5).	[17]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Histone H1.5 (H1-5).	[18]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Histone H1.5 (H1-5).	[19]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Histone H1.5 (H1-5).	[20]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Histone H1.5 (H1-5).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Histone H1.5 (H1-5).	[22]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Histone H1.5 (H1-5).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone H1.5 (H1-5).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone H1.5 (H1-5).	[26]
Nobiletin	DM7R3B6	Preclinical	Nobiletin decreases the expression of Histone H1.5 (H1-5).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone H1.5 (H1-5).	[29]

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 Histone H1.5 (H1-5).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Histone H1.5 (H1-5).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Histone H1.5 (H1-5).	[27]

References

• [1] Molecular analysis of V(H)I+ B lymphocytes in hepatitis C patients.Dig Liver Dis. 2003 Nov;35(11):788-94. doi: 10.1016/s1590-8658(03)00452-3.
• [2] Purification and partial sequencing of inhibitory factor on renal membrane adenylate cyclase in pancreatic cancer extract: identity with histones H1b or H1d.Biochem Biophys Res Commun. 1991 Apr 15;176(1):255-61. doi: 10.1016/0006-291x(91)90917-v.
• [3] Protein-interaction-network-based analysis for genome-wide association analysis of schizophrenia in Han Chinese population.J Psychiatr Res. 2014 Mar;50:73-8. doi: 10.1016/j.jpsychires.2013.11.014. Epub 2013 Dec 13.
• [4] 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.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [10] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [13] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [16] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [17] 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.
• [18] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [19] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [20] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [21] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [22] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [23] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [26] 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.
• [27] 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.
• [28] Characteristics of nobiletin-mediated alteration of gene expression in cultured cell lines. Biochem Biophys Res Commun. 2013 Feb 15;431(3):530-4.
• [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.