Noncanonical Regulation of the Hedgehog Mediator <i>GLI1</i> by c-MYC in Burkitt Lymphoma

Yoon, Joon Won; Gallant, Marisa; Lamm, Marilyn; Iannaccone, Stephen; Vieux, Karl Frederic; Proytcheva, Maria; Hyjek, Elizabeth; Iannaccone, Philip M.; Walterhouse, David

doi:10.1158/1541-7786.mcr-12-0441

Cited by 48 publications

(39 citation statements)

References 34 publications

(35 reference statements)

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“…Thus, our observation that Wnt signaling is important for Myc - but not kras -induced tumorigenesis was also consistent with these previously reported studies. In contrast, although Kras or Myc had been reported to activate hedgehog signaling in malignancies such as pancreatic cancer or lymphoma3839, it appears that Hedgehog signaling is disposable in kras or Myc -induced HCC.…”

Section: Discussionmentioning

confidence: 93%

RETRACTED ARTICLE: Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish

Bai

Yang

Huo

et al. 2017

Sci Rep

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Previously we have generated inducible liver tumor models by transgenic expression of an oncogene and robust tumorigenesis can be rapidly induced by activation of the oncogene in both juvenile and adult fish. In the present study, we aimed at chemical intervention of tumorigenesis for understanding molecular pathways of tumorigenesis and for potential development of a chemical screening tool for anti-cancer drug discovery. Thus, we evaluated the roles of several major signaling pathways in krasV12- or Myc-induced liver tumors by using several small molecule inhibitors: SU5402 and SU6668 for VEGF/FGF signaling; IWR1 and cardionogen 1 for Wnt signaling; and cyclopamine and Gant61 for Hedgehog signaling. Inhibition of VEGF/FGF signaling was found to deter both Myc- and krasV12-induced liver tumorigenesis while suppression of Wnt signaling relaxed only Myc- but not krasV12-induced liver tumorigenesis. Inhibiting Hedgehog signaling did not suppress either krasV12 or Myc-induced tumors. The suppression of liver tumorigenesis was accompanied with a decrease of cell proliferation, increase of apoptosis, distorted liver histology. Collectively, our observations suggested the requirement of VEGF/FGF signaling but not the hedgehog signaling in liver tumorigenesis in both transgenic fry. However, Wnt signaling appeared to be required for liver tumorigenesis only in Myc but not krasV12 transgenic zebrafish.

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Section: Discussionmentioning

confidence: 93%

RETRACTED ARTICLE: Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish

Bai

Yang

Huo

et al. 2017

Sci Rep

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“…23) The protein level of p21 increased by inhibition of the Hh signal by cyclopamine in NB cells. 14) These results suggest that the p21 protein level increase was mediated by GLI2 suppression.…”

Section: Discussionmentioning

confidence: 80%

The GANT61, a GLI Inhibitor, Induces Caspase-Independent Apoptosis of SK-N-LO Cells

Μatsumoto

Tabata

Suzuki

2014

Biological & Pharmaceutical Bulletin

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GANT61 is a small-molecule inhibitor of glioma-associated oncogene 1 (GLI1)- and GLI2-mediated transcription at the nuclear level that exerts its effect by preventing DNA binding. It has been demonstrated to induce cell death against Ewing's sarcoma family tumor (ESFT) cell lines in a dose-dependent manner. The most sensitive cell line was SK-N-LO, which expresses the EWS-FLI1 fusion gene. SK-N-LO cells treated with GANT61 showed cellular and nuclear morphological changes, including cell shrinkage, chromatin condensation and nuclear fragmentation, in a concentration-dependent manner, as visualized by Hoechst 33342 staining. Furthermore, annexin V-propidium iodide (PI) double-staining revealed a significant increase in the number of late apoptotic cells. GANT61 induced a significant decrease in the proportion of cells in the S phase. Significant decrease of the protein levels of GLI2, survivin, cyclin A and claspin, and significant increase of p21 expression was also observed in the cells treated with GANT61. Moreover, poly (ADP-ribose) polymerase (PARP) cleavage was observed, but no cleavage of caspase-3 or -7, or any change in the expressions of Bcl-2 or p53 were observed. These findings suggest that GANT61 induces cell death of SK-N-LO cells in a caspase-independent manner, by inhibiting DNA replication in the S phase.

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“…This is particularly relevant in the SHH subtype. Both MYC (37) and MYCN (38–40) have been reported to interact with and regulate transcription factors involved in SHH signaling, raising the possibility that inhibition of MYC activation may also result in inhibition of the SHH pathway, and other pathways important in the pathogenesis of medulloblastoma.…”

Section: Discussionmentioning

confidence: 99%

BET Bromodomain Inhibition ofMYC-Amplified Medulloblastoma

Bandopadhayay

Bergthold

Nguyen

et al. 2014

Clinical Cancer Research

291

256

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Purpose MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design We evaluated the effects of genetic and pharmacological inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and GEMM-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed down-regulation of MYC expression and confirmed inhibition of MYC-associated transcriptional targets. Exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged survival of orthotopic xenograft models of MYC-amplified medulloblastoma (p<0.001). Xenografts harvested from mice after five doses of JQ1 had reduced expression of MYC mRNA and a reduced proliferative index. Conclusion JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

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Noncanonical Regulation of the Hedgehog Mediator GLI1 by c-MYC in Burkitt Lymphoma

Cited by 48 publications

References 34 publications

RETRACTED ARTICLE: Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish

RETRACTED ARTICLE: Chemical inhibition reveals differential requirements of signaling pathways in krasV12- and Myc-induced liver tumors in transgenic zebrafish

The GANT61, a GLI Inhibitor, Induces Caspase-Independent Apoptosis of SK-N-LO Cells

BET Bromodomain Inhibition ofMYC-Amplified Medulloblastoma

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