Abstract
Activation of the Hedgehog (Hh) signaling pathway has been implicated in a variety of malignancies including neuroblastoma. Expression of Gli1, a downstream effector of Hh, correlates with a favorable prognosis in patients with neuroblastoma. Moreover, Gli1 overexpression reduces mitotic index and induces transcription of genes involved in the differentiation of neuroblastoma cells; however, much remains unknown regarding the regulation of Gli1 transcriptional activity. Here, we report a novel negative regulation of Gli1 transcriptional activity by PI3K/AKT2 signal transduction pathway. Constitutively active PI3K subunit, p110α, inhibited Gli1 transcriptional activity in neuroblastoma cells, whereas, overexpression of an inactive form of PI3K subunit, p85, enhanced its activity. Specifically, the AKT2 isoform inhibited Gli1 luciferase activity. Silencing AKT2 using siRNA increased Gli1 transcriptional activity and conversely, overexpression of constitutively active AKT2 (myr-AKT2) decreased Gli1 transcriptional activity. Furthermore, Gli1 overexpression-mediated decrease in anchorage-independent growth was rescued by AKT2 overexpression. We also demonstrated that AKT2 overexpression regulates the nuclear-cytoplasmic distribution of exogenous Gli1 protein in neuroblastoma cells by relieving a GSK3β-mediated destabilization of SUFU, a negative regulator of Gli1 nuclear translocation. Inhibition of nuclear Gli1 accumulation may explain for the suppression of the tumor-suppressive function of Gli1. Collectively, our findings suggest an important role of Gli1 as a tumor suppressor in neuroblastoma, and offer a mechanism by which AKT2 regulates the subcellular localization, and in turn, inhibits the tumor-suppressive function of Gli1 in neuroblastoma.
Highlights
Neuroblastoma arises from the neural crest elements of the sympathetic nervous system
Our data suggest an inhibitory role for the PI3K/AKT2 signaling on Gli1 transcriptional activity in neuroblastoma cells
Gli1 is necessary and sufficient for disease progression in basal cell carcinoma and medulloblastoma [17, 18]. Neuroblastoma differs from these cancers as Gli1 expression correlates with a more favorable prognosis in patients and induces differentiation of neuroblastoma cells [3, 4]
Summary
Neuroblastoma arises from the neural crest elements of the sympathetic nervous system. As a pediatric neuroendocrine tumor, studying embryonic developmental pathways involved in the fetal nervous system is warranted. Aberrant activation of one such embryonic pathway, Hedgehog (Hh) signaling, is associated with a variety of cancers [1]. Canonical Hh signaling regulates target gene expression by activating transcription factors, namely Gli, Gli and Gli3 [2]. Activation of Hh/Gli signaling has been found in early-stage tumors, and indicates favorable prognosis in neuroblastoma patients [3, 4]. Gli overexpression reduces the mitotic index of neuroblastoma cells, suggesting a tumorsuppressive role of Gli1 [3]. The exact cellular mechanism by which Gli exerts its anti-tumorigenic function in neuroblastoma remains unclear
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