Priority Research Papers:
Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression
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Claudia A. Benavente1, David Finkelstein2, Dianna A. Johnson3,4, Jean-Christophe Marine5, Ruth Ashery-Padan6, Michael A. Dyer1,6,7
1Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
2Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
3Department of Ophtalmology, The University of Tennessee Health Science Center, Memphis, TN, USA
4Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, USA
5Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, Leuven, Belgium
6Department of Human Molecular Genetics and Biochemistry, Tel-Aviv University, Tel Aviv, Israel
7Howard Hughes Medical Institute, Chevy Chase, MD, USA
Michael A. Dyer, e-mail: [email protected]
Keywords: Rb, E2F, HELLS, UHRF1, retinoblastoma, cancer
Received: August 04, 2014 Accepted: September 06, 2014 Published: October 28, 2014
The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK.
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