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

• Published in: Nature (London) Vol. 494; no. 7438; pp. 484 - 488
• Main Authors: Atwood, Scott X., Li, Mischa, Lee, Alex, Tang, Jean Y., Oro, Anthony E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-02-2013; Nature Publishing Group
• Subjects: 631/67/1059; 631/67/1813; 631/67/2329; 692/308/153; Animals; Cancer; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - enzymology; Carcinoma, Basal Cell - metabolism; Carcinoma, Basal Cell - pathology; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Centrosome - metabolism; Drug Resistance, Neoplasm; Feedback, Physiological; Hedgehog Proteins - metabolism; Humanities and Social Sciences; Humans; Identification and classification; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Keratinocytes - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; letter; Mice; multidisciplinary; Observations; Phosphorylation; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein kinases; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Science; Signal Transduction - drug effects; Smoothened Receptor; Testing; Transcription factors; Transcription Factors - metabolism; Zinc Finger Protein GLI1; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11889

Atypical protein kinase C ι/λ is shown to be critical, through its regulation of the transcription factor GLI, for hedgehog-dependent processes, such as the growth of basal cell carcinomas.
New target in hedgehog-dependent carcinomas
Inhibitors of the hedgehog (HH) cell signalling pathway that target the smoothened membrane protein have emerged as a therapy for basal cell carcinomas, but patients often develop resistance. This study identifies atypical protein kinase C ι/λ (aPKC-ι/λ ) as a possible alternative target to smoothened in HH-dependent cancers. Anthony Oro and colleagues show that aPKC-ι/λ is a transcriptional target of HH signalling that, in turn, potentiates HH signalling by promoting the activity of the downstream transcription factor GLI1. aPKC-ι/λ is upregulated in basal cell carcinomas and inhibition of aPKC-ι/λ shows anti-tumour activity in mice with basal cell carcinomas, and also against smoothened inhibitor-resistant carcinoma cells.
Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI
1
. Although inhibitors of membrane protein smoothened (SMO) effectively suppress HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy
1
,
2
,
3
,
4
,
5
,
6
. Here we identify atypical protein kinase C ι/λ (aPKC-ι/λ) as a novel GLI regulator in mammals. aPKC-ι/λ and its polarity signalling partners
7
co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling
8
,
9
. Genetic or pharmacological loss of aPKC-ι/λ 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-ι/λ and SMO control the expression of similar genes in tumour cells. aPKC-ι/λ functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC-ι/λ is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC-ι/λ suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC-ι/λ is critical for HH-dependent processes and implicates aPKC-ι/λ as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers.