Atypical protein kinase C (aPKC) ι/λ acts downstream of smoothened (SMO) to activate GLI1.
Major finding: Atypical protein kinase C (aPKC) ι/λ acts downstream of smoothened (SMO) to activate GLI1.
Clinical relevance: aPKC ι/λ is upregulated in basal cell carcinomas and contributes to SMO inhibitor resistance.
Impact: aPKC ι/λ is a Hedgehog regulator that may be a therapeutic target in basal cell carcinoma.
Basal cell carcinomas are associated with mutations that cause hyperactive Hedgehog pathway signaling. Small-molecule inhibitors of smoothened (SMO), a Hedgehog pathway activator, have been approved for treatment of basal cell carcinoma, but resistance quickly develops. Atwood and colleagues sought to identify alternative druggable Hedgehog pathway targets by using a scaffold protein downstream of SMO as bait in a proteomics screen. One hit was atypical protein kinase C (aPKC) ι/λ, a protein with known roles in regulation of cell polarity and ciliogenesis. aPKC ι/λ inhibition reduced Hedgehog signaling in a dose-dependent manner and led to downregulation of many of the same genes as SMO inhibitors, but a SMO agonist did not induce Hedgehog target gene expression in the presence of an aPKC ι/λ inhibitor, indicating that aPKC ι/λ operates downstream of SMO in Hedgehog signaling. Evaluation of the role of aPKC ι/λ in regulation of GLI transcription factors, which ultimately induce Hedgehog target gene activation, revealed that aPKC ι/λ specifically phosphorylated GLI1 and was required for maximal binding to its target loci. Notably, both GLI1 and PRKCI, the gene encoding aPKC ι/λ, were specifically overexpressed in primary basal cell carcinomas compared with normal human keratinocytes, and levels of phosphorylated, active aPKC ι/λ were elevated in invasive and SMO inhibitor-resistant basal cell carcinomas, suggesting that aPKC ι/λ activity may contribute to basal cell carcinoma progression and drug resistance. Consistent with this possibility, aPKC ι/λ inhibition reduced the growth of both SMO inhibitor-sensitive and SMO inhibitor-resistant basal cell carcinoma cells, and topical application of an aPKC ι/λ inhibitor suppressed the growth of allografted basal cell carcinomas without evidence of acquired resistance. aPKC ι/λ inhibition may thus represent an attractive alternative to SMO inhibition in Hedgehog-dependent cancers and a potentially useful therapeutic strategy for treatment of SMO inhibitor-resistant basal cell carcinomas.