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Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

ABSTRACT: The HEDGEHOG-GLI (HH-GLI) signalling is a key pathway critical in embryonic development, stem cell biology and tissue homeostasis. In recent years, aberrant activation of HH-GLI signalling has been linked to several types of cancer, including those of the skin, brain, lungs, prostate, gastrointestinal tract and blood. HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications. Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling. The identification of this complex crosstalk and the understanding of how the major oncogenic signalling pathways interact in cancer is a crucial step towards the establishment of efficient targeted combinatorial treatments. Here we review recent findings on the cooperative integration of HH-GLI signalling with the major oncogenic inputs and we discuss how these cues modulate the activity of the GLI proteins in cancer. We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

SUBMITTER: Pandolfi S

PROVIDER: S-EPMC4836208 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Pandolfi Silvia S Stecca Barbara B

Expert reviews in molecular medicine 20150209

The HEDGEHOG-GLI (HH-GLI) signalling is a key pathway critical in embryonic development, stem cell biology and tissue homeostasis. In recent years, aberrant activation of HH-GLI signalling has been linked to several types of cancer, including those of the skin, brain, lungs, prostate, gastrointestinal tract and blood. HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose acti ...[more]

PMID: 25660620

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Project description:Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor of many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling profoundly depend on interactions with other pathways such as epidermal growth factor receptor-mediated signaling which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. We demonstrate that the human medulloblastoma cell line Daoy possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic Hedgehog or Smoothened agonist induced expression of GLI1 protein and prevented processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed on the transcriptomic as well as proteomic level. Daoy cells responded to the co-treatment by downregulating GLI1, PTCH, and HHIP on the transcript level which was also seen when Amphiregulin (AREG) was used instead of EGF. The finding that EGFR signaling silences proteins acting as negative regulators of HH signaling is firstly described here as a novel crosstalk mechanism. Furthermore, combined EGFR/HH signaling maintains high GLI1 protein levels contrasting its downregulation on the transcript level. On the other hand, high level synergism was observed with respect to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile pointing to more wide-spread, yet context-dependent, interactions between HH/GLI and growth factor receptor signaling in human malignancies. To study interactions between HH- and EGF-induced signaling, time-resolved measurements were carried out over a period of 24 h at 14 different time points after stimulation by EGF with and without additional stimulation by SHH. Furthermore, as a control, cells without any stimulation by EGF and SHH (control) and cells in the presents of SHH were analyzed. Overall, three biological replicates of 60 different treatment/timepoints were analyzed yielding 180 different samples.

Dataset Information

Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Publications

Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Similar Datasets

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