scholarly journals Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

Oncogene ◽  
2021 ◽  
Author(s):  
Daniel J. García-Domínguez ◽  
Nabil Hajji ◽  
Sara Sánchez-Molina ◽  
Elisabet Figuerola-Bou ◽  
Rocío M. de Pablos ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ewing Sarcoma ◽  
Fusion Gene ◽  
Selective Inhibition ◽  
Oncogenic Driver ◽  
Xenograft Models ◽  
Children And Young Adults ◽  
Specificity Protein ◽  
Therapeutic Alternatives ◽  
Activator Complex

AbstractEwing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.

scholarly journals HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

2021 ◽  
Author(s):  
Daniel J. García-Domínguez ◽  
Nabil Hajji ◽  
Sara Sánchez-Molina ◽  
Elisabet Figuerola-Bou ◽  
Rocío M. de Pablos ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ewing Sarcoma ◽  
Fusion Gene ◽  
Standard Of Care ◽  
Selective Inhibition ◽  
Clinical Samples ◽  
Oncogenic Driver ◽  
Specificity Protein ◽  
Therapeutic Alternatives ◽  
Activator Complex

ABSTRACTEwing sarcoma (EWS) is an aggressive developmental sarcoma driven by a fusion gene, EWSR1-FLI1. However, little is known about the regulation of EWSR1-FLI1 chimeric fusion gene expression. Here, we demonstrate that active nuclear HDAC6 in EWS modulates acetylation status of specificity protein 1 (SP1), consequently regulating SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. Overexpression of HDAC6 in primary EWS tumor clinical samples correlates with a poor prognosis. Notably, a combination treatment of a selective HDAC6 inhibitor and doxorubicin (standard of care in EWS) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for EWS patients.

scholarly journals Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia [see comments]

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 601-607 ◽  
Author(s):  
AM Tari ◽  
SD Tucker ◽  
A Deisseroth ◽  
G Lopez-Berestein
Keyword(s):  
Growth Inhibition ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Hematologic Malignancy ◽  
Control Cell ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Myelogenous Leukemia ◽  
Ph Chromosome

Abstract Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by the presence of the Philadelphia (Ph) chromosome. Bcr- abl, the fusion gene associated with the Ph chromosome, expresses a p210bcr-abl protein that promotes a selective expansion of mature myeloid progenitor cells. Methylphosphonate (MP) oligodeoxynucleotides complementary to specific regions of the bcr-abl mRNA were incorporated in liposomes. We studied the effects of liposomal MP (L-MP) on the growth inhibition of CML-like cell lines. L-MP targeted to the breakpoint junctions of the bcr-abl mRNA inhibited the growth of CML cells. Fifty percent inhibition was achieved at approximately 1 mumol/L of L-MP oligonucleotide concentrations. The inhibitory effect was selective because growth inhibition was observed only with CML but not with control cell lines. Moreover, CML cell growth inhibition was dependent on the sequence of the MP oligodeoxynucleotides incorporated in the liposomes. The growth inhibition of CML cells by L-MP resulted from selective inhibition of the expression of the p210bcr-abl protein.

scholarly journals HOTAIRprimes the Ewing sarcoma family of tumors for tumorigenesis via epigenetic dysregulation involving LSD1

2018 ◽  
Author(s):  
Hasan Siddiqui ◽  
Julia Selich-Anderson ◽  
Joshua Felgenhauer ◽  
James Fitch ◽  
Vijay Nadella ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Ewing Sarcoma ◽  
Colony Formation ◽  
Fusion Gene ◽  
Tumor Xenograft ◽  
Cell Physiology ◽  
Cell Of Origin

AbstractThe EWS-FLI1 fusion protein drives oncogenesis in the Ewing sarcoma family of tumors (ESFT) in humans, but its toxicity in normal cells requires additional cellular events for oncogenesis. We show that the lncRNAHOTAIRmaintains cell viability in the presence of EWS-FLI1 and redirects epigenetic regulation in ESFT.HOTAIRis consistently overexpressed in ESFTs and is not driven by EWS-FLI1. Repression ofHOTAIRin ESFT cell lines significantly reduces anchorage-independent colony formation in vitro and impairs tumor xenograft growth in vivo. Overexpression ofHOTAIRin human mesenchymal stem cells (hMSCs), a putative cell of origin of ESFT, and IMR90 cells induces colony formation. Critically, HOTAIR-expressing hMSCs and IMR90 cells remain viable with subsequentEWS-FLI1expression.HOTAIRinduces histone modifications and gene repression through interaction with the epigenetic modifier LSD1 in ESFT cell lines and hTERT-hMSCs. Our findings suggest thatHOTAIRmaintains ESFT viability through epigenetic dysregulation.SignificanceWhile theEWS-FLI1fusion gene was determined to be the oncogenic driver in the overwhelming majority of ESFT, it is toxic to cell physiology and requires one or more additional molecular events to maintain cell viability. As these tumors have surprisingly few genetic mutations at diagnosis, epigenetic changes have been considered to be such an event, but the mechanism by which these changes are driven remains unclear. Our work shows thatHOTAIRis consistently expressed among ESFT and induces epigenetic and gene expression changes that cooperate in tumorigenesis. Furthermore, expression ofHOTAIRallows for cell viability in the setting of subsequentEWS-FLI1expression. Our findings elucidate new steps of malignant transformation in this cancer and identify novel therapeutic targets.

scholarly journals Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia [see comments]

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 601-607 ◽  
Author(s):  
AM Tari ◽  
SD Tucker ◽  
A Deisseroth ◽  
G Lopez-Berestein
Keyword(s):  
Growth Inhibition ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Hematologic Malignancy ◽  
Control Cell ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Myelogenous Leukemia ◽  
Ph Chromosome

Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by the presence of the Philadelphia (Ph) chromosome. Bcr- abl, the fusion gene associated with the Ph chromosome, expresses a p210bcr-abl protein that promotes a selective expansion of mature myeloid progenitor cells. Methylphosphonate (MP) oligodeoxynucleotides complementary to specific regions of the bcr-abl mRNA were incorporated in liposomes. We studied the effects of liposomal MP (L-MP) on the growth inhibition of CML-like cell lines. L-MP targeted to the breakpoint junctions of the bcr-abl mRNA inhibited the growth of CML cells. Fifty percent inhibition was achieved at approximately 1 mumol/L of L-MP oligonucleotide concentrations. The inhibitory effect was selective because growth inhibition was observed only with CML but not with control cell lines. Moreover, CML cell growth inhibition was dependent on the sequence of the MP oligodeoxynucleotides incorporated in the liposomes. The growth inhibition of CML cells by L-MP resulted from selective inhibition of the expression of the p210bcr-abl protein.

scholarly journals Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 5171-5179 ◽  
Author(s):  
Pascal Gelebart ◽  
Mona Anand ◽  
Hanan Armanious ◽  
Anthea C. Peters ◽  
Jennifer Dien Bard ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Selective Inhibition ◽  
Canonical Pathway ◽  
Oligonucleotide Arrays ◽  
Downstream Target ◽  
Naturally Occurring ◽  
Inactive Form ◽  
Mantle Cell

Abstract Aberrations of the Wnt canonical pathway (WCP) are known to contribute to the pathogenesis of various types of cancer. We hypothesize that these defects may exist in mantle cell lymphoma (MCL). Both the upstream and downstream aspects of WCP were examined in MCL cell lines and tumors. Using WCP-specific oligonucleotide arrays, we found that MCL highly and consistently expressed Wnt3 and Wnt10. β-catenin, a transcriptional factor that is a downstream target of WCP, is localized to the nucleus and transcriptionally active in all 3 MCL cell lines examined. By immunohistochemistry, 33 (52%) of 64 MCL tumors showed nuclear localization of β-catenin, which significantly correlated with the expression of the phosphorylated/inactive form of GSK3β (p-GSK3β; P = .011, Fisher). GSK3β inactivation is directly linked to WCP stimulation, since addition of recombinant sFRP proteins (a naturally occurring decoy for the Wnt receptors) resulted in a significant decrease in p-GSK3β. Down-regulation of DvL-2 (an upstream signaling protein in WCP) by siRNA or selective inhibition of β-catenin using quercetin significantly decreased cell growth in MCL cell lines. To conclude, WCP is constitutively activated in a subset of MCL and it appears to promote tumorigenesis in MCL.

Primitive Neuroectodermal Tumor of the Stomach

2005 ◽  
Vol 129 (1) ◽  
pp. 107-110 ◽  
Author(s):  
Raoulin Soulard ◽  
Valère Claude ◽  
Philippe Camparo ◽  
Jean-Philippe Dufau ◽  
Patrick Saint-Blancard ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Young Adults ◽  
Soft Tissue ◽  
Ewing Sarcoma ◽  
Primitive Neuroectodermal Tumor ◽  
Neuron Specific Enolase ◽  
Neuroectodermal Tumor ◽  
Chain Reaction ◽  
Children And Young Adults ◽  
Polymerase Chain

Abstract Ewing sarcoma/primitive neuroectodermal tumor is classically a tumor of the soft tissue or bone in children and young adults, but several cases have been described in patients of all ages. Within the last decade, the clinicopathologic spectrum of Ewing sarcoma/primitive neuroectodermal tumor has been markedly expanded by recognition that the tumor may also have a visceral origin. We describe a case of primitive neuroectodermal tumor arising in the stomach of a 66-year-old woman. The neoplasm was excised using a radical surgical procedure. Microscopically, the tumor was made up of solid nests and sheets of round cells. Immunohistochemically, the tumor cells showed immunoreactivity for CD99, S100, neuron-specific enolase, and vimentin. A multiplex real-time polymerase chain reaction assay detected an EWS-ERG fusion. To our knowledge, this is the first description of a primitive neuroectodermal tumor arising in the stomach.

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