02 2013
Nature published our paper on aPKC-dependent Gli activation in basal cell carcinomas
Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI1. Although inhibitors
of membrane protein smoothened (SMO) effectively suppress
HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C iota/lambda (aPKC) as a novel GLI regulator in mammals.
aPKC and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC
function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows
that aPKC and SMO control the expression of similar genes in tumour cells. aPKC functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC
is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC is critical for HH-dependent processes and implicates aPKC
as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers. Congratulations to all the authors on a job well done!
