GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas

Abstract

Basal cell carcinoma (BCC) growth requires high levels of Hedgehog (Hh) signaling through the transcription factor Gli1. While inhibitors of membrane protein Smoothened (Smo) effectively suppress Hh signaling, early tumor resistance illustrates the need for additional downstream targets for therapy1–6. Here we identify atypical Protein Kinase C iota/lambda (aPKC) as a novel Gli regulator. aPKC and its polarity signaling partners7 colocalize at the centrosome and form a complex with Missing-in-Metastasis (MIM), a scaffolding protein that potentiates Hh signaling8,9. Genetic or pharmacological loss of aPKC function blocks Hh signaling and proliferation of BCC cells. aPKC is a Hh target gene that forms a positive feedback loop with Gli and exhibits elevated levels in BCCs. Genome-wide transcriptional profiling shows that aPKC and Smo control the expression of similar genes in tumor 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 tumors and targeting aPKC suppresses signaling and growth of resistant BCC cell lines. These results demonstrate aPKC is critical for Hh-dependent processes and implicates aPKC as a new, tumor-selective therapeutic target for the treatment of Smo-inhibitor resistant cancers.