Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA2TBWS)

• DOT Name: High mobility group nucleosome-binding domain-containing protein 3 (HMGN3)
• Synonyms: Thyroid receptor-interacting protein 7; TR-interacting protein 7; TRIP-7
• Gene Name: HMGN3
• Related Disease: Depression
• UniProt ID: HMGN3_HUMAN
• Pfam ID: PF01101
• Sequence:
  MPKRKSPENTEGKDGSKVTKQEPTRRSARLSAKPAPPKPEPKPRKTSAKKEPGAKISRGA
  KGKKEEKQEAGKEGTAPSENGETKAEEAQKTESVDNEGE
• Function: Binds to nucleosomes, regulating chromatin structure and consequently, chromatin-dependent processes such as transcription, DNA replication and DNA repair. Affects both insulin and glucagon levels and modulates the expression of pancreatic genes involved in insulin secretion. Regulates the expression of the glucose transporter SLC2A2 by binding specifically to its promoter region and recruiting PDX1 and additional transcription factors. Regulates the expression of SLC6A9, a glycine transporter which regulates the glycine concentration in synaptic junctions in the central nervous system, by binding to its transcription start site. May play a role in ocular development and astrocyte function.
• Tissue Specificity: Expressed in kidney, lung, pancreas, testis, skeletal muscle, heart, thyroid gland, pituitary gland, prostate and uterus. Low expression in liver, spleen, placenta and ovaries.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Depression	DIS3XJ69	Strong	Genetic Variation	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	High mobility group nucleosome-binding domain-containing protein 3 (HMGN3) affects the response to substance of Paclitaxel.	[20]
Topotecan	DMP6G8T	Approved	High mobility group nucleosome-binding domain-containing protein 3 (HMGN3) affects the response to substance of Topotecan.	[20]
Vinblastine	DM5TVS3	Approved	High mobility group nucleosome-binding domain-containing protein 3 (HMGN3) affects the response to substance of Vinblastine.	[20]

2 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 High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of High mobility group nucleosome-binding domain-containing protein 3 (HMGN3).	[19]

References

• [1] Construction and dissection of the ceRNAceRNA network reveals critical modules in depression.Mol Med Rep. 2019 May;19(5):3411-3420. doi: 10.3892/mmr.2019.10009. Epub 2019 Mar 5.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.