Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma.

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.

Inhibition of the oncogenic fusion protein EWS-FLI1 causes G-M cell cycle arrest and enhanced vincristine sensitivity in Ewing's sarcoma.

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.

African-American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks.

Background: Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), the subtype that shows marked variation in geographic frequency. The molecular architecture of African-American ESCC is still poorly understood.

A new sub-pathway of long-patch base excision repair involving 5' gap formation.

Base excision repair (BER) is one of the most frequently used cellular DNA repair mechanisms and modulates many human pathophysiological conditions related to DNA damage. Through live cell and reconstitution experiments, we have discovered a major sub-pathway of conventional long-patch BER that involves formation of a 9-nucleotide gap 5' to the lesion. This new sub-pathway is mediated by RECQ1 DNA helicase and ERCC1-XPF endonuclease in cooperation with PARP1 poly(ADP-ribose) polymerase and RPA The novel gap formation step is employed during repair of a variety of DNA lesions, including oxidative and alkylation damage.

Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells.

Ezrin is a scaffolding protein that is involved in oncogenesis by linking cytoskeletal and membrane proteins. Ezrin interacts with epidermal growth factor receptor (EGFR) in the cell membrane, but little is known about the effects of this interaction on EGFR signaling pathway. In this study, we established the biological and functional significance of ezrin-EGFR interaction in non-small cell lung cancer (NSCLC) cells.

YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model.

Ewing sarcoma is an aggressive tumor of bone and soft tissue affecting predominantly children and young adults. Tumor-specific chromosomal translocations create EWS-FLI1 and similar aberrant ETS fusion proteins that drive sarcoma development in patients. ETS family fusion proteins and over-expressed ETS proteins are also found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients.

Ezrin Binds to DEAD-Box RNA Helicase DDX3 and Regulates Its Function and Protein Level.

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.

Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.

The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based on proteins that modulate splice site selection. EWS-FLI1 is an Ewing sarcoma (ES) oncoprotein with an interactome that we demonstrate to have multiple partners in spliceosomal complexes.

RNA helicase A activity is inhibited by oncogenic transcription factor EWS-FLI1.

RNA helicases impact RNA structure and metabolism from transcription through translation, in part through protein interactions with transcription factors. However, there is limited knowledge on the role of transcription factor influence upon helicase activity. RNA helicase A (RHA) is a DExH-box RNA helicase that plays multiple roles in cellular biology, some functions requiring its activity as a helicase while others as a protein scaffold.

Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing Sarcoma.

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.

RETRACTED: Combining PARP-1 inhibition and radiation in Ewing sarcoma results in lethal DNA damage.

Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas.

Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma.

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.

Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1.

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.

Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity.

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.

Single enantiomer of YK-4-279 demonstrates specificity in targeting the oncogene EWS-FLI1.

Oncogenic fusion proteins, such as EWS-FLI1, are excellent therapeutic targets as they are only located within the tumor. However, there are currently no agents targeted toward transcription factors, which are often considered to be 'undruggable.' A considerable body of evidence is accruing that refutes this claim based upon the intrinsic disorder of transcription factors.

Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors.

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.

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

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.

A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma.

Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design.