Sonic hedgehog signaling in Basal cell nevus syndrome

Abstract

The hedgehog (Hh) signaling pathway is considered to be a major signal transduction pathway during embryonic development, but it usually shuts down after birth. Aberrant Sonic hedgehog (Shh) activation during adulthood leads to neoplastic growth. Basal cell carcinoma (BCC) of the skin is driven by this pathway. Here, we summarize information related to the pathogenesis of this neoplasm, discuss pathways that crosstalk with Shh signaling, and the importance of the primary cilium in this neoplastic process. The identification of the basic/translational components of Shh signaling has led to the discovery of potential mechanism-driven druggable targets and subsequent clinical trials have confirmed their remarkable efficacy in treating BCCs, particularly in patients with nevoid BCC syndrome (NBCCS), an autosomal dominant disorder in which patients inherit a germline mutation in the tumor-suppressor gene Patched (Ptch). Patients with NBCCS develop dozens to hundreds of BCCs due to derepression of the downstream G-protein-coupled receptor Smoothened (SMO). Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expression of transcription factors Glis that drive cell proliferation and tumor growth. Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in patients with NBCCS, which finally led to its FDA approval in 2012.

Figure-1. Primary Cilium and Activation of the Hh Signaling Pathway

Inactivating mutations in PTCH or binding of Hh ligands to PTCH de-represses SMO thereby allowing its translocation onto the tip of the primary cilium leading to transcriptional activation of Gli1/2. Multiple ciliary proteins are involved in processing Hh signal transduction. Ciliary EVC/EVC2 forms a complex with SMO that in turn is tethered by a complex of EFCAB7 and IQCE anchoring the EVC-EVC2 complex in a signaling microdomain at the base of the primary cilium. Activation and nuclear translocation of Gli1/2 involves dissociation of Gli1/2 from its endogenous inhibitor, SuFu. Kif7 cooperates with SuFu in catalyzing dissociation of the Sufu-Gli2 complex. Inhibition of Hh binding to Ptch by robotnikinin or blocking of SMO activation by small molecules such as cyclopamine, itraconazole, vismodegib, LDE225, etc. inhibits Hh signaling and tumor growth. While ATO blocks translocation of Gli2 to the tip of cilia, GANT61 and GANT 58 inhibit Gli1/2 transcriptional activities. Gli^A, Gli activator.

Figure-2. Hh Pathway Crosstalk with Other Signaling Pathways

The Hh signaling pathway demonstrates complex crosstalk with multiple signaling pathways that modulate cancer pathogenesis. The TNF-mTOR pathway activates Gli1 in a SMO-independent manner. Activated mTOR enhances Gli1 transcriptional activity and oncogenic functions via S6K1-mediated Gli1 phosphorylation at Ser84 which helps to release Gli1 from SUFU. IGF/PI3K/Akt pathway regulates Gli1/2 activities involving modulation of PKA-dependent phosphorylation of Glis, and so are the EGFR/MEK/ERK or TGFβ signaling pathways. In addition, TGFβ can directly induce Gli2 expression independent of Hh signaling and requires Smad3. Wnt signaling also modulates Hh activity although the underlying cascade remains unclear. Coding region determinant-binding protein (CRD-BP), a direct target of Wnt/βCatenin signaling, can bind with Gli1 mRNA promoting tumor growth. Hh signaling can also regulate Wnt signaling through modulation of βCatenin. Atypical protein kinase C ι/λ (aPKC-ι/λ) acts downstream of SMO to phosphorylate and activate Gli1, resulting in its maximal DNA binding and transcriptional activation. Gli^A, Gli activator; Gli^R, Gli repressor; TCF, T-cell factor; LEF, lymphoid enhancer binding factor.