Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma

Regl, Gerhard; Neill, Graham W.; Eichberger, Thomas; Kasper, Maria; Ikram, Mohammed S.; Koller, Josef; Hintner, Helmut; Quinn, Anthony G.; Frischauf, Anna‐Maria; Aberger, Fritz

doi:10.1038/sj.onc.1205748

Cited by 186 publications

(205 citation statements)

References 51 publications

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“…To screen for immunomodulatory cytokines and/or growth factors able to cooperate with HH/GLI signaling (Fig 1 a ) in oncogenic transformation, we used nontumorigenic, human keratinocytes (HaCaT) with doxycycline‐inducible GLI1 expression 24. Importantly, GLI1 expressing keratinocytes do not display a fully transformed phenotype but require additional cooperative signals for malignant growth 25.…”

Section: Resultsmentioning

confidence: 99%

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Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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Section: Resultsmentioning

confidence: 99%

“…Doxycycline (Dox)‐inducible GLI1‐expressing HaCaT keratinocytes and mouse BCC cell line ASZ00122 were grown as described previously 23, 24. Induction of GLI1 expression in HaCaT keratinocytes was done as reported in Refs.…”

Section: Methodsmentioning

confidence: 99%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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“…The positive effect of GLI on cell-cycle progression is dependent on JUN Recently, GLI1 and GLI2 were shown to promote cellcycle progression and antagonize contact inhibition in HaCaT keratinocytes (Regl et al, 2002). We found activation of cell-cycle markers such as cyclin D1 and E2F1 by GLI2act and JUN (Table 1), which prompted us to analyse whether GLI can stimulate S-phase entry in epidermal cells in the absence of JUN.…”

Section: Co-immunoprecipitation (Coip) Of Gli1 or Gli2act And Jun Promentioning

confidence: 93%

“…Having shown that expression of GLI1 and GLI2act in cultured keratinocytes leads to an increase in JUN mRNA and protein, we investigated JUN expression in BCC, which shows strong expression of HH pathway components PTCH, GLI1 and GLI2 (Hahn et al, 1996;Johnson et al, 1996;Ghali et al, 1999;Regl et al, 2002). We measured the mRNA levels of JUN, GLI1, GLI2 and PTCH by qRT-PCR in samples of human BCC (n ¼ 6) and normal human skin (n ¼ 3) (Figure 2a).…”

Section: Jun Expression Is Increased In Response To Gli In Human Keramentioning

confidence: 99%

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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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Surgical Excision After Neoadjuvant Therapy With Vismodegib for a Locally Advanced Basal Cell Carcinoma and Resistant Basal Carcinomas in Gorlin Syndrome

et al. 2013

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Vismodegib is useful to treat locally advanced or metastatic basal cell carcinomas (BCCs), 1 but to our knowledge, its use as a neoadjuvant to shrink BCCs before surgery has not been reported. This case illustrates the role of vismodegib as a neoadjuvant agent. In addition, this case highlights the fact that a patient with Gorlin syndrome can develop resistant BCCs while taking vismodegib, a phenomenon not widely recognized although recently reported. 2

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Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma

Cited by 186 publications

References 51 publications

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

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

Surgical Excision After Neoadjuvant Therapy With Vismodegib for a Locally Advanced Basal Cell Carcinoma and Resistant Basal Carcinomas in Gorlin Syndrome

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