Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT75I1UH)

• DOT Name: Epithelial-stromal interaction protein 1 (EPSTI1)
• Gene Name: EPSTI1
• Related Disease:
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Triple negative breast cancer
  Advanced cancer
• UniProt ID: ESIP1_HUMAN
• Sequence:
  MNTRNRVVNSGLGASPASRPTRDPQDPSGRQGELSPVEDQREGLEAAPKGPSRESVVHAG
  QRRTSAYTLIAPNINRRNEIQRIAEQELANLEKWKEQNRAKPVHLVPRRLGGSQSETEVR
  QKQQLQLMQSKYKQKLKREESVRIKKEAEEAELQKMKAIQREKSNKLEEKKRLQENLRRE
  AFREHQQYKTAEFLSKLNTESPDRSACQSAVCGPQSSTWKLPILPRDHSWARSWAYRDSL
  KAEENRKLQKMKDEQHQKSELLELKRQQQEQERAKIHQTEHRRVNNAFLDRLQGKSQPGG
  LEQSGGCWNMNSGNSWGI
• Function: Plays a role in M1 macrophage polarization and is required for the proper regulation of gene expression during M1 versus M2 macrophage differentiation. Might play a role in RELA/p65 and STAT1 phosphorylation and nuclear localization upon activation of macrophages.
• Tissue Specificity: Highly expressed in placenta, small intestine, spleen, kidney, thymus, liver, salivary gland and testes. Weakly expressed in breast, skeletal muscle and colon. Highly expressed in breast cancer upon interaction between tumor cells and stromal cells in vitro. Expressed in blood mononuclear cells from patients with systemic lupus erythematosus (SLE).
• Reactome Pathway: RND1 GTPase cycle (R-HSA-9696273)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Epithelial-stromal interaction protein 1 (EPSTI1).	[14]

2 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 Epithelial-stromal interaction protein 1 (EPSTI1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Epithelial-stromal interaction protein 1 (EPSTI1).	[18]

References

• [1] Regulation of inflammatory gene expression in macrophages by epithelial-stromal interaction 1 (Epsti1).Biochem Biophys Res Commun. 2018 Feb 5;496(2):778-783. doi: 10.1016/j.bbrc.2017.12.014. Epub 2017 Dec 5.
• [2] circEPSTI1 regulates ovarian cancer progression via decoying miR-942.J Cell Mol Med. 2019 May;23(5):3597-3602. doi: 10.1111/jcmm.14260. Epub 2019 Mar 19.
• [3] Breast cancer genes PSMC3IP and EPSTI1 play a role in apoptosis regulation.PLoS One. 2015 Jan 15;10(1):e0115352. doi: 10.1371/journal.pone.0115352. eCollection 2015.
• [4] 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.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] 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.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] 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.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] 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.
• [18] 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.
• [19] 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.