Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor

Roeb, Wendy; Boyer, Antonia; Cavenee, Webster K.; Arden, Karen C.

doi:10.4161/cc.7.7.5652

Cited by 15 publications

(9 citation statements)

References 26 publications

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“…In addition, efficient induction of apoptotic aRMS cell death upon PAX3/FKHR depletion occurs, at least in part, through p21 since its depletion can rescue from apoptosis. Given that PAX3/FKHR can destabilize the transcription factor EGR1 (Roeb et al, 2007;Roeb et al, 2008) and that EGR1 itself was shown to modulate p21 transcription (Ragione et al, 2003), we hypothesized that EGR1 is critically involved in p21 activation upon PAX3/FKHR depletion. This conclusion is supported by several lines of evidence: First, EGR1 and p21 protein expression levels are reduced in a series of translocation positive aRMS tumor cell lines as compared to human myoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…However, as it could be shown that PAX3/FKHR rather than EGR1 is ubiquitinated (Roeb et al, 2008), strategies that exploit proteasome inhibition might also lead to increased protein levels of transcriptional active PAX3/FKHR in aRMS tumor cells. Therefore, we propose combination strategies of PKC412 with HDAC inhibitors such as VPA, as this cotreatment results in reactivation of the EGR1 target p21 and in reduction of the transcriptional activity of PAX3/FKHR.…”

Section: Discussionmentioning

confidence: 99%

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p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS) which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease.Recently, we were able to demonstrate that the small molecule inhibitor PKC412 (midostaurin) exhibits strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR.Here, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase (HDAC) inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo.We provide evidence that the antitumor effect upon combination treatment is achieved by VPAinduced reactivation of p21 which is downregulated in aRMS cells via destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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“…Therefore, camptothecin seems to inhibit transcriptional activity by directly downregulating the protein level of PF. PF has previously been shown to be ubiqutinated [31]. Because proteasome inhibitors are potent at inducing cell death in both ARMS and ERMS cells [32], we could not directly examine the effect of proteasome inhibitors on camptothecin-induced inhibition of ARMS cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

PAX3–FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis

et al. 2009

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Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). By high-throughput screening, we identified camptothecin as an ARMS-selective inhibitor. Camptothecin more efficiently inhibited proliferation and induced apoptosis in Rh30 (ARMS) than RD (ERMS) cells. Ectopic expression of the PAX3-FKHR (PF) fusion protein in RD cells significantly increased sensitivity, whereas siRNA knockdown of PF decreased sensitivity of Rh30 cells to camptothecin. The sensitization required a transcriptionally active PF, and camptothecin downregulated levels of PF protein. These findings suggest that it is feasible to develop agents that preferentially block the growth of ARMS.

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“…Reexpression of EGR1 in some of these cells leads to growth arrest, differentiation or cell death, indicating that EGR1 has a fundamental role in the biology of these tumors. Recent studies of the PAX3-FOXO1 fusion oncoprotein in alveolar rhabdomyosarcoma have shown that PAX3-FOXO1 inhibits cell cycle arrest by attenuating the expression of p57kip2 (CDKN1C), an EGR1 target gene (Roeb et al, 2007(Roeb et al, , 2008. Interestingly, in this tumor, EGR1 expression is not affected, but the fusion oncoprotein interacts with EGR1 and promotes its degradation; neither of the wild-type constituents of the fusion oncoprotein interact with EGR1.…”

Section: Discussionmentioning

confidence: 99%

EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

Cheng

Sampaio

et al. 2010

Oncogene

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Synovial sarcoma is a high-grade soft tissue malignancy, for which current cytotoxic chemotherapies provide limited benefit. Although histone deacetylase (HDAC) inhibitors are known to suppress synovial sarcoma in vitro and in vivo, the exact mechanism is not clear. In this study, we report a central role of the transcription factor, early growth response-1 (EGR1), in the regulation of HDAC inhibitorinduced apoptotic cell death in synovial sarcoma. The SS18-SSX oncoprotein, characteristic of synovial sarcoma, maintains EGR1 expression at low levels, whereas it is significantly increased after HDAC inhibitor treatment. On the contrary, EGR1 knockdown leads to a decrease in HDAC inhibitor-induced apoptosis. Moreover, we find that under these conditions phosphatase and tensin homolog deleted in chromosome 10 (PTEN) is upregulated and this occurs through direct binding of EGR1 to an element upstream of the PTEN promoter. Using a combination of gain-and loss-of-function approaches, we show that EGR1 modulation of PTEN contributes to HDAC inhibitorinduced apoptosis in synovial sarcoma. Finally, restoration of EGR1 or PTEN expression is sufficient to induce synovial sarcoma cell death. Taken together, our findings indicate that SS18-SSX-mediated attenuation of an EGR1-PTEN network regulates synovial sarcoma cell survival, and that HDAC inhibitor-mediated apoptosis operates at least in part through reactivation of this pathway.

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Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor

Abstract: Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor, Cell Cycle,7:7,[837][838][839][840][841] DOI: 10.4161/cc.7.7.5652 To link to this article: https://doi.org/10.4161/cc.7.7.5652

Cited by 15 publications

References 26 publications

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

PAX3–FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis

EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

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