Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVTKJ4I)

• DOT Name: Epithelial splicing regulatory protein 2 (ESRP2)
• Synonyms: RNA-binding motif protein 35B; RNA-binding protein 35B
• Gene Name: ESRP2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pituitary adenoma
  Isolated cleft lip
  Renal cell carcinoma
  Advanced cancer
• UniProt ID: ESRP2_HUMAN
• Sequence:
  MTPPPPPPPPPGPDPAADPAADPCPWPGSLVVLFGATAGALGRDLGSDETDLILLVWQVV
  EPRSRQVGTLHKSLVRAEAAALSTQCREASGLSADSLARAEPLDKVLQQFSQLVNGDVAL
  LGGGPYMLCTDGQQLLRQVLHPEASRKNLVLPDMFFSFYDLRREFHMQHPSTCPARDLTV
  ATMAQGLGLETDATEDDFGVWEVKTMVAVILHLLKEPSSQLFSKPEVIKQKYETGPCSDS
  TVPCPYSSKADVVDSETVVRARGLPWQSSDQDVARFFKGLNVARGGVALCLNAQGRRNGE
  ALIRFVDSEQRDLALQRHKHHMGVRYIEVYKATGEEFVKIAGGTSLEVARFLSREDQVIL
  RLRGLPFSAGPTDVLGFLGPECPVTGGTEGLLFVRHPDGRPTGDAFALFACEELAQAALR
  RHKGMLGKRYIELFRSTAAEVQQVLNRYASGPLLPTLTAPLLPIPFPLAPGTGRDCVRLR
  GLPYTATIEDILSFLGEAAADIRPHGVHMVLNQQGRPSGDAFIQMTSAERALAAAQRCHK
  KVMKERYVEVVPCSTEEMSRVLMGGTLGRSGMSPPPCKLPCLSPPTYTTFQATPTLIPTE
  TAALYPSSALLPAARVPAAPTPVAYYPGPATQLYLNYTAYYPSPPVSPTTVGYLTTPTAA
  LASAPTSVLSQSGALVRMQGVPYTAGMKDLLSVFQAYQLPADDYTSLMPVGDPPRTVLQA
  PKEWVCL
• Function: mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Also regulates the splicing of CD44, CTNND1, ENAH, 3 transcripts that undergo changes in splicing during the epithelial-to-mesenchymal transition (EMT). Acts by directly binding specific sequences in mRNAs. Binds the GU-rich sequence motifs in the ISE/ISS-3, a cis-element regulatory region present in the mRNA of FGFR2.
• Tissue Specificity: Epithelial cell-specific.
• Reactome Pathway: FGFR2 alternative splicing (R-HSA-6803529)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Pituitary adenoma	DISJ5R1X	Strong	Biomarker	[6]
Isolated cleft lip	DIS2O2JV	moderate	Biomarker	[7]
Renal cell carcinoma	DISQZ2X8	moderate	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Epithelial splicing regulatory protein 2 (ESRP2).	[19]

1 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 splicing regulatory protein 2 (ESRP2).	[17]

References

• [1] Genome-wide screen for differentially methylated long noncoding RNAs identifies Esrp2 and lncRNA Esrp2-as regulated by enhancer DNA methylation with prognostic relevance for human breast cancer.Oncogene. 2017 Nov 16;36(46):6446-6461. doi: 10.1038/onc.2017.246. Epub 2017 Jul 31.
• [2] Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways.EMBO Rep. 2019 Feb;20(2):e46078. doi: 10.15252/embr.201846078. Epub 2019 Jan 21.
• [3] A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes.Cell Rep. 2018 May 8;23(6):1639-1650. doi: 10.1016/j.celrep.2018.04.031.
• [4] Epithelial splicing regulatory protein 1 and 2 paralogues correlate with splice signatures and favorable outcome in human colorectal cancer.Oncotarget. 2016 Nov 8;7(45):73800-73816. doi: 10.18632/oncotarget.12070.
• [5] ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.Oncogenesis. 2017 Oct 9;6(10):e389. doi: 10.1038/oncsis.2017.87.
• [6] Long-noncoding RNA IFNG-AS1 exerts oncogenic properties by interacting with epithelial splicing regulatory protein 2 (ESRP2) in pituitary adenomas.Pathol Res Pract. 2018 Dec;214(12):2054-2061. doi: 10.1016/j.prp.2018.09.023. Epub 2018 Sep 29.
• [7] Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.Am J Hum Genet. 2018 Jun 7;102(6):1143-1157. doi: 10.1016/j.ajhg.2018.04.009. Epub 2018 May 24.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] 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.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.