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

Nature volume 494, pages 484–488 (2013)Cite this article

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Abstract

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 therapy1,2,3,4,5,6. 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 partners7 co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling8,9. 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.

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Figure 1: aPKC-ι/λ is a centrosome-associated protein that regulates HH signalling.
Figure 2: aPKC-ι/λ and HH form a positive-feedback loop in BCCs.
Figure 3: aPKC-ι/λ phosphorylates and activates GLI1.
Figure 4: Topical aPKC inhibitor suppresses primary tumour growth.

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Acknowledgements

We would like to thank K. Qun for bioinformatics assistance, J. Kim for archival BCC tissue, A. Chang and S. Aasi for clinical trial operations, K. Chang for technical assistance, and H. Chang and P. Khavari for reading the manuscript. This work was supported by NIH NRSA 1F32CA14208701 (S.X.A.) and NIH grants AR052785 and AR046786 (A.E.O.).

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  1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Scott X. Atwood, Mischa Li, Alex Lee, Jean Y. Tang & Anthony E. Oro

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  1. Scott X. Atwood
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Contributions

S.X.A. and A.E.O. designed the experiments. S.X.A. performed the experiments. M.L. aided the biochemical and knockdown analyses. A.L. and J.Y.T. performed the allograft BCC drug treatments. J.Y.T. provided vismodegib-resistant tumour samples. S.X.A. and A.E.O. wrote the manuscript.

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Correspondence to Scott X. Atwood or Anthony E. Oro.

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Competing interests

A.E.O. is a clinical investigator for trials funded by Genentech and Novartis.

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Atwood, S., Li, M., Lee, A. et al. GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas. Nature 494, 484–488 (2013). https://doi.org/10.1038/nature11889

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