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

Claudia A Benavente,David Finkelstein,Michael A Dyer,Dianna A Johnson,Ruth Ashery-Padan,Jean-Christophe Marine

doi:10.18632/oncotarget.2468

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.

Highlights

The Rb protein and its two related family members (p107 and p130) regulate gene expression through interactions with E2F/DP heterodimeric transcription factors [1]
We found that retinal differentiation defects and tumorigenesis following loss of the Rb family occurs as two independent events that rely on distinct E2f family members
To determine if loss of other E2f family members expressed in the retina can prevent tumorigenesis or rescue the developmental defect in the Rb;p107 deficient mice, we developed Chx10-Cre;RbLox/ Lox;p107−/−;E2f1−/− (E2f1 TKO), Chx10-Cre;RbLox/ Lox;p107−/−;E2f3Lox/Lox (E2f3 TKO), Chx10-Cre;RbLox/ Lox;p107−/−;E2f4−/− (E2f4 TKO), and Chx10-Cre;RbLox/ Lox;p107−/−;E2f5Lox/Lox (E2f5 TKO) triple-knockout mice

Summary

Introduction

The Rb protein and its two related family members (p107 and p130) regulate gene expression through interactions with E2F/DP heterodimeric transcription factors [1]. While Rb, p107, and p130 show overlapping but distinct preferences for particular E2F family members to regulate transcription, it has been proposed that they may shift depending on the cellular context. Some cells express different constellations of Rb or E2F family members and this can lead to distinct regulation [2]. When a gene is inactivated or overexpressed, the Rb/E2Fs may shift their binding preferences [3]. Beyond these differences, there are distinct mechanisms of action. A major question in the field is how Rb/E2F interactions control proliferation and tumor suppression in coordination with cellular differentiation events

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Conclusion