The FBXO4 Tumor Suppressor Functions as a Barrier to Braf^V600E-Dependent Metastatic Melanoma

Abstract

Cyclin D1–cyclin-dependent kinase 4/6 (CDK4/6) dysregulation is a major contributor to melanomagenesis. Clinical evidence has revealed that p16^INK4A, an allosteric inhibitor of CDK4/6, is inactivated in over half of human melanomas, and numerous animal models have demonstrated that p16^INK4A deletion promotes melanoma. FBXO4, a specificity factor for the E3 ligase that directs timely cyclin D1 proteolysis, has not been studied in melanoma. We demonstrate that Fbxo4 deficiency induces Braf-driven melanoma and that this phenotype depends on cyclin D1 accumulation in mice, underscoring the importance of this ubiquitin ligase in tumor suppression. Furthermore, we have identified a substrate-binding mutation, FBXO4 I377M, that selectively disrupts cyclin D1 degradation while preserving proteolysis of the other known FBXO4 substrate, TRF1. The I377M mutation and Fbxo4 deficiency result in nuclear accumulation of cyclin D1, a key transforming neoplastic event. Collectively, these data provide evidence that FBXO4 dysfunction, as a mechanism for cyclin D1 overexpression, is a contributor to human malignancy.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00706-13.

ACKNOWLEDGMENTS

We thank Trish Brafford of The Wistar Institute for melanoma cell lines and guidance; Keith Flaherty, Patricia Van Belle, and David Elder for assistance in tumor collection; Xuedong Liu for anti-TRF1 serum; and Madhavi Vaddi at the Penn Genomics Facility, Quian-Chen Yu, the Histology Core Facility, and the Animal Core Facility for excellent technical assistance.

The work was supported by the Abramson Cancer Center at the University of Pennsylvania and National Institutes of Health grants CA133154, R25 CA101871-07, and P50CA093372. Services provided in the Penn Genomics Facility are supported by Abramson Cancer Center core grant 5P30CA016520.