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Article ; Online: Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma.

Erkizan, Hayriye Verda / Sukhadia, Shrey / Natarajan, Thanemozhi G / Marino, Gustavo / Notario, Vicente / Lichy, Jack H / Wadleigh, Robert G

Scientific reports

2021 Volume 11, Issue 1, Page(s) 14814

Abstract: Esophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are of African descent. ...

Abstract	Esophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are of African descent. African American ESCC (AA ESCC) is particularly aggressive, and its biological underpinnings remain poorly understood. We sought to identify the genomic abnormalities by conducting whole exome sequencing of 10 pairs of matched AA esophageal squamous cell tumor and control tissues. Genomic analysis revealed diverse somatic mutations, copy number alterations (SCNAs), and potential cancer driver genes. Exome variants created two subgroups carrying either a high or low tumor mutation burden. Somatic mutational analysis based on the Catalog of Somatic Mutations in Cancer (COSMIC) detected SBS16 as the prominent signature in the high mutation rate group suggesting increased DNA damage. SBS26 was also detected, suggesting possible defects in mismatch repair and microsatellite instability. We found SCNAs in multiple chromosome segments, encoding MYC on 8q24.21, PIK3CA and SOX2 on 3q26, CCND1, SHANK2, CTTN on 11q13.3, and KRAS on 12p12. Amplifications of EGFRvIII and EGFRvIVa mutants were observed in two patients, representing a novel finding in ESCC that has potential clinical relevance. This present exome sequencing, which to our knowledge, represents the first comprehensive exome analysis exclusively in AA ESCC, and highlights novel mutated loci that might explain the aggressive nature of AA ESCC and lead to the development of diagnostic and prognostic markers as well as therapeutic targets.
MeSH term(s)	African Americans/genetics ; Case-Control Studies ; DNA Copy Number Variations ; DNA Mutational Analysis/methods ; Esophageal Neoplasms/genetics ; Esophageal Squamous Cell Carcinoma/genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Whole Exome Sequencing/methods
Language	English
Publishing date	2021-07-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-94064-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma.

Erkizan, Hayriye V / Uversky, Vladimir N / Toretsky, Jeffrey A

Clinical cancer research : an official journal of the American Association for Cancer Research

2010 Volume 16, Issue 16, Page(s) 4077–4083

Abstract: Targeted therapy for cancer, which is specifically directed toward the cancer without any potential for effects outside of controlling the tumor, is a gold standard for treatment. Ewing's sarcoma contains the potential target EWS-FLI1, as a result of a ... ...

Abstract	Targeted therapy for cancer, which is specifically directed toward the cancer without any potential for effects outside of controlling the tumor, is a gold standard for treatment. Ewing's sarcoma contains the potential target EWS-FLI1, as a result of a pathognomonic chromosomal translocation. The EWS-FLI1 fusion protein includes the EWS domain, a potent transcriptional activator alongside the highly conserved FLI1 ets DNA-binding domain. Because of the combination of these domains, the EWS-FLI1 fusion protein acts as an aberrant transcription factor whose expression results in cellular transformation. EWS-FLI1 functions by binding to normal cellular protein partners in transcription and splicing, similar to how a virus would corrupt normal cellular machinery for virion production. Therefore, understanding the protein-protein interactions of EWS-FLI1 and the pathways that are regulated by these partnerships will inform both oncogenesis and therapeutics. This review describes the known protein partners and transcriptional targets of EWS-FLI1, while proposing strategies for exploiting these partnerships with targeted therapy.
MeSH term(s)	Animals ; Gene Expression Regulation, Neoplastic ; Humans ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Proto-Oncogene Protein c-fli-1 ; RNA-Binding Protein EWS ; Sarcoma, Ewing/genetics ; Sarcoma, Ewing/metabolism ; Sarcoma, Ewing/pathology ; Signal Transduction/physiology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic ; Translocation, Genetic
Chemical Substances	EWS-FLI fusion protein ; Oncogene Proteins, Fusion ; Proto-Oncogene Protein c-fli-1 ; RNA-Binding Protein EWS ; Transcription Factors
Language	English
Publishing date	2010-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-09-2261
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Article ; Online: Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma.

Carmody Soni, Emily E / Schlottman, Silke / Erkizan, Hayriye V / Uren, Aykut / Toretsky, Jeffrey A

Clinical orthopaedics and related research

2013 Volume 472, Issue 3, Page(s) 874–882

Abstract: Background: Most synovial sarcomas contain a chromosomal translocation t(X;18), which results in the formation of an oncoprotein SS18-SSX critical to the viability of synovial sarcoma.: Questions/purposes: We (1) established and characterized three ... ...

Abstract	Background: Most synovial sarcomas contain a chromosomal translocation t(X;18), which results in the formation of an oncoprotein SS18-SSX critical to the viability of synovial sarcoma. Questions/purposes: We (1) established and characterized three novel synovial sarcoma cell lines and asked (2) whether inhibition of SS18-SSX1 decreases cell viability in these cell lines; and (3) whether reduction in viability after SS18-SSX1 knockdown is caused by apoptosis. After identifying a specific posttranscriptional splice variant in our cell lines, we asked (4) whether this provides a survival benefit in synovial sarcoma. Methods: Cells lines were characterized. SS18-SSX1 knockdown was achieved using a shRNA system. Cell viability was assessed by WST-1 analysis and apoptosis examined by caspase-3 activity. Results: We confirmed the SS18-SSX1 translocation in all cell lines and identified a consistent splicing variant. We achieved successful knockdown of SS18-SSX1 and with this saw a significant reduction in cell viability. Decreased viability was a result of increased apoptosis. Reintroduction of the exon 8 sequence into cells reduced cell viability in all cell lines. Conclusions: We confirmed the presence of the SS18-SSX1 translocation in our cell lines and its importance in the survival of synovial sarcoma. We have also demonstrated that reduction in cell viability is related to an increase in apoptosis. In addition, we have identified a potential mediator of SS18-SSX function in exon 8. Clinical relevance: SS18-SSX represents a tumor-specific target in synovial sarcoma. Exploitation of SS18-SSX and its protein partners will allow us to develop potent tumor-specific therapeutic agents.
MeSH term(s)	Adult ; Apoptosis ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival ; Child ; Down-Regulation ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Male ; Middle Aged ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; RNA Interference ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Sarcoma, Synovial/genetics ; Sarcoma, Synovial/metabolism ; Sarcoma, Synovial/pathology ; Signal Transduction ; Translocation, Genetic
Chemical Substances	Neoplasm Proteins ; Oncogene Proteins, Fusion ; Proto-Oncogene Proteins ; Repressor Proteins ; SS18 protein, human ; SS18-SSX1 fusion protein ; SYT-SSX fusion protein ; synovial sarcoma X breakpoint proteins (164289-47-8) ; CASP3 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2013-05-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	80301-7
ISSN	1528-1132 ; 0009-921X
ISSN (online)	1528-1132
ISSN	0009-921X
DOI	10.1007/s11999-013-3065-9
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Article ; Online: Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1.

Abaan, Ogan D / Hendriks, Wiljan / Uren, Aykut / Toretsky, Jeffrey A / Erkizan, Hayriye V

Experimental cell research

2012 Volume 319, Issue 1, Page(s) 1–11

Abstract: Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings sarcoma (ES) inhibit cell growth ...

Abstract	Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.
MeSH term(s)	Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; Animals ; Bone Neoplasms/enzymology ; Bone Neoplasms/pathology ; Catalysis ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Cells, Cultured ; Fibroblasts ; HEK293 Cells ; Humans ; Mice ; Mice, Mutant Strains ; Pancreatic Neoplasms/enzymology ; Pancreatic Neoplasms/pathology ; Protein Tyrosine Phosphatase, Non-Receptor Type 13/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 13/metabolism ; Sarcoma, Ewing/enzymology ; Sarcoma, Ewing/pathology ; Substrate Specificity/physiology ; Valosin Containing Protein
Chemical Substances	Cell Cycle Proteins ; Protein Tyrosine Phosphatase, Non-Receptor Type 13 (EC 3.1.3.48) ; Ptpn13 protein, mouse (EC 3.1.3.48) ; Adenosine Triphosphatases (EC 3.6.1.-) ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6) ; Vcp protein, mouse (EC 3.6.4.6)
Language	English
Publishing date	2012-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.09.003
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Article ; Online: Inhibition of the oncogenic fusion protein EWS-FLI1 causes G

Zöllner, Stefan K / Selvanathan, Saravana P / Graham, Garrett T / Commins, Ryan M T / Hong, Sung Hyeok / Moseley, Eric / Parks, Sydney / Haladyna, Jessica N / Erkizan, Hayriye V / Dirksen, Uta / Hogarty, Michael D / Üren, Aykut / Toretsky, Jeffrey A

Science signaling

2017 Volume 10, Issue 499

Abstract: Ewing's sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 ( ... ...

Abstract	Ewing's sarcoma (ES) is a rare and highly malignant cancer that grows in the bones or surrounding tissues mostly affecting adolescents and young adults. A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), which is generated from a chromosomal translocation, is implicated in driving most ES cases by modulation of transcription and alternative splicing. The small-molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis in ES cells. We aimed to identify both the underlying mechanism of the drug and potential combination therapies that might enhance its antitumor activity. We tested 69 anticancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G
MeSH term(s)	Apoptosis/drug effects ; Apoptosis/genetics ; Cell Line, Tumor ; Cyclin B1/genetics ; Cyclin B1/metabolism ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; G2 Phase Cell Cycle Checkpoints/drug effects ; G2 Phase Cell Cycle Checkpoints/genetics ; Humans ; Indoles/pharmacology ; M Phase Cell Cycle Checkpoints/drug effects ; M Phase Cell Cycle Checkpoints/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Oncogene Proteins, Fusion/antagonists & inhibitors ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Proto-Oncogene Protein c-fli-1/antagonists & inhibitors ; Proto-Oncogene Protein c-fli-1/genetics ; Proto-Oncogene Protein c-fli-1/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA-Binding Protein EWS/antagonists & inhibitors ; RNA-Binding Protein EWS/genetics ; RNA-Binding Protein EWS/metabolism ; Sarcoma, Ewing/drug therapy ; Sarcoma, Ewing/genetics ; Sarcoma, Ewing/metabolism ; Sarcoma, Ewing/pathology ; Ubiquitin-Conjugating Enzymes/genetics ; Ubiquitin-Conjugating Enzymes/metabolism ; Vincristine/pharmacology
Chemical Substances	BCL2 protein, human ; CCNB1 protein, human ; Cyclin B1 ; EWS-FLI fusion protein ; Indoles ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Oncogene Proteins, Fusion ; Proto-Oncogene Protein c-fli-1 ; Proto-Oncogene Proteins c-bcl-2 ; RNA-Binding Protein EWS ; YK 4-279 ; Vincristine (5J49Q6B70F) ; UBE2C protein, human (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23)
Language	English
Publishing date	2017-10-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aam8429
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Article: Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1

Abaan, Ogan D / Hendriks, Wiljan / Üren, Aykut / Toretsky, Jeffrey A / Erkizan, Hayriye V

Experimental cell research. 2013 Jan. 1, v. 319, no. 1

2013

Abstract	Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.
Keywords	carcinogenesis ; catalytic activity ; cell growth ; cytokinesis ; fibroblasts ; mass spectrometry ; mice ; mutants ; neoplasm cells ; oncogenes ; phosphorylation ; protein-tyrosine-phosphatase ; sarcoma ; transcription (genetics) ; transcription factors ; tyrosine
Language	English
Dates of publication	2013-0101
Size	p. 1-11.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.09.003
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity.

Schlottmann, Silke / Erkizan, Hayriye V / Barber-Rotenberg, Julie S / Knights, Chad / Cheema, Amrita / Uren, Aykut / Avantaggiati, Maria L / Toretsky, Jeffrey A

Frontiers in oncology

2012 Volume 2, Page(s) 107

Abstract: Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor ... ...

Abstract	Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor growth. However, its regulation is still enigmatic. To date, no functionally significant post-translational modifications of EWS-FLI1 have been shown. Since ES are sensitive to histone deacetylase inhibitors (HDI), and these inhibitors are advancing in clinical trials, we sought to identify if EWS-FLI1 is directly acetylated. We convincingly show acetylation of the C-terminal FLI1 (FLI1-CTD) domain, which is the DNA binding domain of EWS-FLI1. In vitro acetylation studies showed that acetylated FLI1-CTD has higher DNA binding activity than the non-acetylated protein. Over-expression of PCAF or treatment with HDI increased the transcriptional activity of EWS-FLI1, when co-expressed in Cos7 cells. However, our data that evaluates the acetylation of full-length EWS-FLI1 in ES cells remains unclear, despite creating acetylation specific antibodies to four potential acetylation sites. We conclude that EWS-FLI1 may either gain access to chromatin as a result of histone acetylation or undergo regulation by direct acetylation. These data should be considered when patients are treated with HDAC inhibitors. Further investigation of this phenomenon will reveal if this potential acetylation has an impact on tumor response.
Language	English
Publishing date	2012-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X ; 2234-943X
ISSN (online)	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2012.00107
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Article ; Online: Ezrin Binds to DEAD-Box RNA Helicase DDX3 and Regulates Its Function and Protein Level.

Çelik, Haydar / Sajwan, Kamal P / Selvanathan, Saravana P / Marsh, Benjamin J / Pai, Amrita V / Kont, Yasemin Saygideger / Han, Jenny / Minas, Tsion Z / Rahim, Said / Erkizan, Hayriye Verda / Toretsky, Jeffrey A / Üren, Aykut

Molecular and cellular biology

2015 Volume 35, Issue 18, Page(s) 3145–3162

Abstract: Ezrin is a key regulator of cancer metastasis that links the extracellular matrix to the actin cytoskeleton and regulates cell morphology and motility. We discovered a small-molecule inhibitor, NSC305787, that directly binds to ezrin and inhibits its ... ...

Abstract	Ezrin is a key regulator of cancer metastasis that links the extracellular matrix to the actin cytoskeleton and regulates cell morphology and motility. We discovered a small-molecule inhibitor, NSC305787, that directly binds to ezrin and inhibits its function. In this study, we used a nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS-MS)-based proteomic approach to identify ezrin-interacting proteins that are competed away by NSC305787. A large number of the proteins that interact with ezrin were implicated in protein translation and stress granule dynamics. We validated direct interaction between ezrin and the RNA helicase DDX3, and NSC305787 blocked this interaction. Downregulation or long-term pharmacological inhibition of ezrin led to reduced DDX3 protein levels without changes in DDX3 mRNA. Ectopic overexpression of ezrin in low-ezrin-expressing osteosarcoma cells caused a notable increase in DDX3 protein levels. Ezrin inhibited the RNA helicase activity of DDX3 but increased its ATPase activity. Our data suggest that ezrin controls the translation of mRNAs preferentially with a structured 5' untranslated region, at least in part, by sustaining the protein level of DDX3 and/or regulating its function. Therefore, our findings suggest a novel function for ezrin in regulation of gene translation that is distinct from its canonical role as a cytoskeletal scaffold at the cell membrane.
MeSH term(s)	Adamantane/analogs & derivatives ; Adamantane/pharmacology ; Animals ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Cell Line, Tumor ; Chromatography, Liquid ; Cytoskeletal Proteins/antagonists & inhibitors ; Cytoskeletal Proteins/metabolism ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Humans ; Mice ; Osteosarcoma/genetics ; Osteosarcoma/metabolism ; Osteosarcoma/pathology ; Protein Binding/drug effects ; Protein Biosynthesis/genetics ; Proteomics ; Quinolines/pharmacology ; RNA Interference ; RNA, Messenger/genetics ; RNA, Small Interfering ; Surface Plasmon Resonance ; Tandem Mass Spectrometry
Chemical Substances	Cytoskeletal Proteins ; NSC305787 ; Quinolines ; RNA, Messenger ; RNA, Small Interfering ; ezrin ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; Adamantane (PJY633525U)
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00332-15
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Article ; Online: Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors.

Erkizan, Hayriye V / Scher, Lauren J / Gamble, S Ellen / Barber-Rotenberg, Julie S / Sajwan, Kamal P / Üren, Aykut / Toretsky, Jeffrey A

Cell cycle (Georgetown, Tex.)

2011 Volume 10, Issue 19, Page(s) 3397–3408

Abstract: Ewing tumor is driven by the oncogenic EWS-FLI1 fusion protein that functions as an aberrant transcription factor. The identification of EWS-FLI1 protein partners is essential to enhance its vulnerability as a therapeutic target. We utilized phage ... ...

Abstract	Ewing tumor is driven by the oncogenic EWS-FLI1 fusion protein that functions as an aberrant transcription factor. The identification of EWS-FLI1 protein partners is essential to enhance its vulnerability as a therapeutic target. We utilized phage display library screening against recombinant EWS-FLI1 protein. We identified 27 unique Ewing sarcoma binding peptides. The cytotoxicity evaluation of these peptides with in EWS-FLI1 containing cell lines yielded one potent peptide called ESAP1 (TMRGKKKRTRAN). ESAP1 binds EWS-FLI1 with 0.202 micromolar affinity as measured in surface plasmon resonance. The minimal interaction region of ESAP1 is characterized and found that the lysine residues are critical for cellular cytotoxicity. ESAP1 reduces the transcriptional activity of EWS-FLI1 as well as disrupts cell cycle kinetics in Ewing Tumor cells. These findings provide both a novel experimental probe and a potential therapeutic scaffold for Ewing Tumor.
MeSH term(s)	Amino Acid Sequence ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Humans ; Kinetics ; Oncogene Proteins, Fusion/antagonists & inhibitors ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Peptide Library ; Peptides/metabolism ; Protein Binding ; Proto-Oncogene Protein c-fli-1/antagonists & inhibitors ; Proto-Oncogene Protein c-fli-1/genetics ; Proto-Oncogene Protein c-fli-1/metabolism ; RNA-Binding Protein EWS/antagonists & inhibitors ; RNA-Binding Protein EWS/genetics ; RNA-Binding Protein EWS/metabolism ; Recombinant Fusion Proteins/antagonists & inhibitors ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Sarcoma, Ewing/pathology ; Surface Plasmon Resonance ; Transcriptional Activation
Chemical Substances	EWS-FLI fusion protein ; Oncogene Proteins, Fusion ; Peptide Library ; Peptides ; Proto-Oncogene Protein c-fli-1 ; RNA-Binding Protein EWS ; Recombinant Fusion Proteins
Language	English
Publishing date	2011-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.10.19.17734
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Article ; Online: Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing Sarcoma.

Hong, Sung-Hyeok / Youbi, Sarah E / Hong, S Peter / Kallakury, Bhaskar / Monroe, Phillip / Erkizan, Hayriye V / Barber-Rotenberg, Julie S / Houghton, Peter / Üren, Aykut / Toretsky, Jeffrey A

Oncotarget

2014 Volume 5, Issue 2, Page(s) 338–350

Abstract: Transcription factors have long been deemed 'undruggable' targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for ... ...

Abstract	Transcription factors have long been deemed 'undruggable' targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWS-FLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial.
MeSH term(s)	Animals ; Antineoplastic Agents/blood ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Female ; Humans ; Indoles/blood ; Indoles/pharmacokinetics ; Indoles/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Oncogene Proteins, Fusion/antagonists & inhibitors ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Proto-Oncogene Protein c-fli-1/antagonists & inhibitors ; Proto-Oncogene Protein c-fli-1/genetics ; Proto-Oncogene Protein c-fli-1/metabolism ; RNA-Binding Protein EWS/antagonists & inhibitors ; RNA-Binding Protein EWS/genetics ; RNA-Binding Protein EWS/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Sarcoma, Ewing/drug therapy ; Sarcoma, Ewing/genetics ; Sarcoma, Ewing/metabolism ; Sarcoma, Ewing/pathology ; Transcription, Genetic ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; EWS-FLI fusion protein ; Indoles ; Oncogene Proteins, Fusion ; Proto-Oncogene Protein c-fli-1 ; RNA-Binding Protein EWS ; YK 4-279
Language	English
Publishing date	2014-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.1495
Database	MEDical Literature Analysis and Retrieval System OnLINE

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