Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNCS4SL)

• DOT Name: Epithelial splicing regulatory protein 1 (ESRP1)
• Synonyms: RNA-binding motif protein 35A; RNA-binding protein 35A
• Gene Name: ESRP1
• Related Disease:
  Breast neoplasm
  Pancreatic cancer
  Acromegaly
  Adenoma
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Colitis
  Colonic neoplasm
  Epithelial ovarian cancer
  Estrogen-receptor positive breast cancer
  Germ cell tumor
  Immunodeficiency
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Precancerous condition
  Prostate cancer
  Renal cell carcinoma
  Sensorineural hearing loss disorder
  Teratoma
  Triple negative breast cancer
  Hearing loss, autosomal recessive 109
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Pancreatic ductal carcinoma
  Pancreatic tumour
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Lung adenocarcinoma
  Melanoma
  Metastatic melanoma
  Persistent fetal circulation syndrome
• UniProt ID: ESRP1_HUMAN
• PDB ID: 2DHA; 2RVJ; 7VKI; 7VKJ; 7WRN
• Sequence:
  MTASPDYLVVLFGITAGATGAKLGSDEKELILLFWKVVDLANKKVGQLHEVLVRPDQLEL
  TEDCKEETKIDVESLSSASQLDQALRQFNQSVSNELNIGVGTSFCLCTDGQLHVRQILHP
  EASKKNVLLPECFYSFFDLRKEFKKCCPGSPDIDKLDVATMTEYLNFEKSSSVSRYGASQ
  VEDMGNIILAMISEPYNHRFSDPERVNYKFESGTCSKMELIDDNTVVRARGLPWQSSDQD
  IARFFKGLNIAKGGAALCLNAQGRRNGEALVRFVSEEHRDLALQRHKHHMGTRYIEVYKA
  TGEDFLKIAGGTSNEVAQFLSKENQVIVRMRGLPFTATAEEVVAFFGQHCPITGGKEGIL
  FVTYPDGRPTGDAFVLFACEEYAQNALRKHKDLLGKRYIELFRSTAAEVQQVLNRFSSAP
  LIPLPTPPIIPVLPQQFVPPTNVRDCIRLRGLPYAATIEDILDFLGEFATDIRTHGVHMV
  LNHQGRPSGDAFIQMKSADRAFMAAQKCHKKNMKDRYVEVFQCSAEEMNFVLMGGTLNRN
  GLSPPPCKLPCLSPPSYTFPAPAAVIPTEAAIYQPSVILNPRALQPSTAYYPAGTQLFMN
  YTAYYPSPPGSPNSLGYFPTAANLSGVPPQPGTVVRMQGLAYNTGVKEILNFFQGYQYAT
  EDGLIHTNDQARTLPKEWVCI
• 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. Regulates splicing and expression of genes involved in inner ear development, auditory hair cell differentiation, and cell fate specification in the cochlear epithelium.
• Tissue Specificity: Epithelial cell-specific.
• Reactome Pathway:
  FGFR2 alternative splicing (R-HSA-6803529)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Definitive	Altered Expression	[1]
Pancreatic cancer	DISJC981	Definitive	Biomarker	[2]
Acromegaly	DISCC73U	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Colitis	DISAF7DD	Strong	Genetic Variation	[5]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Germ cell tumor	DIS62070	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[10]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Precancerous condition	DISV06FL	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[12]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[13]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[14]
Teratoma	DIS6ICY4	Strong	Biomarker	[15]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[16]
Hearing loss, autosomal recessive 109	DISRO9CL	Moderate	Autosomal recessive	[14]
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[18]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[17]
Pancreatic tumour	DIS3U0LK	moderate	Altered Expression	[17]
Breast cancer	DIS7DPX1	Limited	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[19]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[18]
Melanoma	DIS1RRCY	Limited	Altered Expression	[20]
Metastatic melanoma	DISSL43L	Limited	Posttranslational Modification	[21]
Persistent fetal circulation syndrome	DISSDYEX	Limited	Genetic Variation	[22]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Epithelial splicing regulatory protein 1 (ESRP1) affects the response to substance of Etoposide.	[36]
Topotecan	DMP6G8T	Approved	Epithelial splicing regulatory protein 1 (ESRP1) affects the response to substance of Topotecan.	[36]

13 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 1 (ESRP1).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[26]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[27]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[28]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[34]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Epithelial splicing regulatory protein 1 (ESRP1).	[35]

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 1 (ESRP1).	[31]

References

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• [4] ESRP1 Induces Cervical Cancer Cell G1-Phase Arrest Via Regulating Cyclin A2 mRNA Stability.Int J Mol Sci. 2019 Jul 29;20(15):3705. doi: 10.3390/ijms20153705.
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• [6] RNA-binding motif protein 35A is a novel tumor suppressor for colorectal cancer.Cell Cycle. 2009 Feb 1;8(3):490-7. doi: 10.4161/cc.8.3.7679. Epub 2009 Feb 22.
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• [8] Esrp1 is a marker of mouse fetal germ cells and differentially expressed during spermatogenesis.PLoS One. 2018 Jan 11;13(1):e0190925. doi: 10.1371/journal.pone.0190925. eCollection 2018.
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• [14] ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development. Dev Cell. 2017 Nov 6;43(3):318-331.e5. doi: 10.1016/j.devcel.2017.09.026. Epub 2017 Oct 26.
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• [17] Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases.Oncogene. 2014 Sep 4;33(36):4485-95. doi: 10.1038/onc.2013.392. Epub 2013 Sep 30.
• [18] Epithelial Splicing Regulatory Protein 1 Inhibits the Invasion and Metastasis of Lung Adenocarcinoma.Am J Pathol. 2018 Aug;188(8):1882-1894. doi: 10.1016/j.ajpath.2018.04.012. Epub 2018 May 24.
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• [20] Altered Expression and Splicing of ESRP1 in Malignant Melanoma Correlates with Epithelial-Mesenchymal Status and Tumor-Associated Immune Cytolytic Activity.Cancer Immunol Res. 2016 Jun;4(6):552-61. doi: 10.1158/2326-6066.CIR-15-0255. Epub 2016 Apr 4.
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• [26] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
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• [32] 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.
• [33] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [34] 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.
• [35] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [36] 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.