Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression.

Abstract

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.

• Authors: Claudia A Benavente, David Finkelstein, Dianna A Johnson, Jean-Christophe Marine, Ruth Ashery-Padan, Michael A Dyer
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 20 Pg. 9594-608 (Oct 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25338120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CCAAT-Enhancer-Binding Proteins
• Chromatin
• E2F1 Transcription Factor
• E2F1 protein, human
• E2F3 Transcription Factor
• E2F3 protein, human
• Eye Proteins
• Homeodomain Proteins
• Intracellular Signaling Peptides and Proteins
• MicroRNAs
• PAX6 Transcription Factor
• PAX6 protein, human
• Paired Box Transcription Factors
• Pax6 protein, mouse
• Repressor Proteins
• UHRF1 protein, human
• Ubiquitin-Protein Ligases
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Syk protein, mouse
• DNA Helicases
• HELLS protein, human

Topics

• Animals
• CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
• Carcinogenesis (genetics, metabolism, pathology)
• Cell Differentiation (physiology)
• Cell Line, Tumor
• Chromatin (genetics, metabolism)
• DNA Helicases (genetics, metabolism)
• Disease Progression
• E2F1 Transcription Factor (genetics)
• E2F3 Transcription Factor (genetics)
• Eye Proteins (genetics, metabolism)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Heterografts
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• PAX6 Transcription Factor
• Paired Box Transcription Factors (genetics, metabolism)
• Protein-Tyrosine Kinases (genetics)
• Repressor Proteins (genetics, metabolism)
• Retinal Neoplasms (genetics, metabolism, pathology)
• Retinoblastoma (genetics, metabolism, pathology)
• Syk Kinase
• Transfection
• Ubiquitin-Protein Ligases