Abstract PR07: Recruitment of Pontin/Reptin by E2F1 amplifies E2F transcriptional response during cancer progression

Abstract

Abstract Unrestricted E2F activity and increased E2F1 expression are hallmarks of liver cancer, but the consequences of aberrant E2F activity for liver cancer progression remain ill defined. Our data show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially triggers a robust gene expression program associated with the cell cycle and predominantly driven by E2f2 and E2f3. During liver cancer progression, slowly accumulating E2f1 recruits a Pontin/Reptin complex to insert the H2a.z histone variant and open the chromatin conformation at E2f1-bound target genes. This epigenetic mechanism amplifies the E2f transcriptional response, leading to enhanced transactivation of cell cycle genes and de novo activation of low binding affinity E2f target genes that regulate non-cell cycle oncogenic features, such as the Warburg effect. In addition, extensive mouse genetic approaches indicate that E2f-driven liver cancer initiation and progression is cell type specific, suggesting that a permissive chromatin environment is necessary to enable E2f oncogenic functions. Collectively, these data indicate that sustained E2F activity expands E2F transcriptional response and connects the regulation of cell cycle with multiple non cell cycle functions that drive tumor progression. This abstract is also being presented as Poster B13. Citation Format: Amy Tarangelo, Nathanael Lo, Rebecca Teng, Eunsun Kim, Pichai Raman, Patrick Viatour. Recruitment of Pontin/Reptin by E2F1 amplifies E2F transcriptional response during cancer progression. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR07.