GLI transcription factors: Mediators of oncogenic Hedgehog signalling

Kasper, Maria; Regl, Gerhard; Frischauf, Anna‐Maria; Aberger, Fritz

doi:10.1016/j.ejca.2005.08.039

Cited by 337 publications

(309 citation statements)

References 86 publications

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“…The involvement of HH or GLI1 in cancer is well established (Kasper et al, 2006). In sarcomas in adults, the grade of tumor has been shown to correlate with the level of GLI1 expression (Stein et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

The EWS/FLI1 oncogenic transcription factor deregulates GLI1

et al. 2007

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Ewing family tumors (EFT), classically Ewing's sarcoma and peripheral primitive neuroectodermal tumor, share a common class of tumor-specific fusion genes thought to be key mediators of tumor biology. Here we demonstrate that the most common Ewing's fusion, EWS/FLI1, produces transcriptional upregulation of GLI1 and its direct transcriptional target PATCHED1 in a model transformation system. This deregulation of GLI1 is common to other EWS/ets chimera and depends on the functional transcriptional regulatory domains. Inhibition of GLI1 via RNAi or via overexpression of endogenous inhibitors results in a reduction of EWS/FLI1 transformation activity. Activation of GLI1 appears to occur in a Hedgehog-independent fashion as blockade of Hedgehog signaling has only a modest effect on EFT cells. We present evidence that EWS/FLI1 upregulation of cMYC may play a role in the upregulation of GLI1 in EWS/ FLI1-transformed NIH3T3 cells. Finally, we demonstrate that observations made in a model transformation system translate to an Ewing cellular background. EFT cell lines express GLI1 and PATCHED and this expression is EWS/FLI1 dependent. Inhibition of GLI1 expression via RNAi results in reduced anchorage-independent growth in an EFT cell line. GLI1 appears to be a transcriptionally deregulated target of EWS/FLI1 that mediates a portion of its tumorigenic phenotype.

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Section: Discussionmentioning

confidence: 99%

The EWS/FLI1 oncogenic transcription factor deregulates GLI1

et al. 2007

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“…Overexpression of either transcription factor in the epidermis and hair follicles of transgenic mice is sufficient to induce skin BCC-like tumors (Grachtchouk et al, 2000;Nilsson et al, 2000). By regulating genes implicated in tumor progression, GLI factors transform normal epithelial cells into tumor cells in a relatively direct fashion (reviewed in Altaba et al (2002); Kasper et al (2006)), without the need for other multiple genetic changes. For instance, several studies identified Snail1 as an early and direct transcriptional response gene of GLI1 (Louro et al, 2002;Karhadkar et al, 2004;Li et al, 2006Li et al, , 2007Fiaschi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma

et al. 2011

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CYLD is a deubiquitination enzyme that regulates different cellular processes, such as cell proliferation and cell survival. Mutation and loss of heterozygosity of the CYLD gene causes development of cylindromatosis, a benign tumour originating from the skin. Our study shows that CYLD expression is dramatically downregulated in basal cell carcinoma (BCC), the most common cancer in humans. Reduced CYLD expression in basal cell carcinoma was mediated by GLI1-dependent activation of the transcriptional repressor Snail. Inhibition of GLI1 restored the CYLD expression-mediated Snail signaling pathway, and caused a significant delay in the G1 to S phase transition, as well as proliferation. Our data suggest that GLI1-mediated suppression of CYLD has a significant role in basal cell carcinoma progression.

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“…In contrast to GLI2 and GLI3, GLI1 is not directly activated by HH signaling but is itself a transcriptional target gene of GLI2 and GLI3. A wealth of data has shown that stability, cellular localization and transcriptional activity of GLI proteins are regulated by several phosphorylation events and by other interacting proteins (reviewed in Hooper and Scott, 2005;Huangfu and Anderson, 2006;Ingham and McMahon, 2001;Kasper et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

et al. 2009

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Sustained Hedgehog (HH) signaling is implicated in basal cell carcinoma of the skin and other types of cancer. Here we show that GLI1 and GLI2, the main transcriptional activators of the HH pathway, directly regulate expression of the activator protein 1 (AP-1) family member JUN, a transcription factor controlling keratinocyte proliferation and skin homeostasis. Activation of the JUN promoter by GLI is dependent on a GLI-binding site and the AP-1 sites known to be involved in self-activation of JUN. Transcription of JUN is greatly enhanced in the presence of GLI and requires activated JUN protein.GLI2act is a more potent activator than GLI1 in these experiments and physical interaction with phosphorylated JUN was only detected for GLI2act. The synergistic effect of GLI and JUN extends to the activation of further GLI target genes as shown by shRNA-mediated knockdown of JUN in human keratinocytes. Some of these cooperatively activated genes are involved in cell-cycle progression, which is consistent with a significant reduction of the proliferative potential of GLI in the absence of JUN. These results suggest a novel connection between HH/GLI pathway activity and JUN, which may contribute to the oncogenic activity of HH/GLI signaling in skin.

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GLI transcription factors: Mediators of oncogenic Hedgehog signalling

Cited by 337 publications

References 86 publications

The EWS/FLI1 oncogenic transcription factor deregulates GLI1

The EWS/FLI1 oncogenic transcription factor deregulates GLI1

GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

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