Abstract B26: Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage

The transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced-stage metastatic and chemoresistant cancers contributes essentially to malignant progression and characterizes the aggressive potential of a tumor. Conceptually, this requires a subset of malignant cells capable of evading apoptotic death through anticancer drugs. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. Here we report a novel function for enhancer of polycomb homolog 1 (EPC1) in DNA damage protection. Depletion of EPC1 potentiates E2F1-mediated apoptosis in response to genotoxic treatment and abolishes tumor cell motility. We found that E2F1 directly binds and activates the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin and inhibits death-inducing targets including p27 and Bim. Mechanistically, we observed that EPC1 is required for recruitment of Tip60, a subunit of the NuA4 acetyltransferase complex, to E2F sites of the Bcl-2 promoter, causing increased activating histone acetylation levels. In contrast, ablation of EPC1 removes the PRC2 component EZH2 from the p27 promoter, resulting in decreased histone methylation for E2F1-mediated gene activation. In this scenario, EPC1 acts as a crucial bridging factor to connect E2F1 with essential components of the chromatin remodeling complexes Nu4A and PRC2. The uncovered cooperativity between EPC1 and E2F1 triggers a gene signature in advanced cancers that predicts metastatic behavior and poor patient survival. These findings unveil a novel oncogenic function of EPC1 for inducing the switch into tumor progression-relevant gene expression that may help to set novel therapies. This work was supported by German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.). Note: This abstract was not presented at the conference. Citation Format: David Engelmann, Yajie Wang, Vijay Alla, Deborah Goody, Shailendra K. Gupta, Alf Spitschak, Brigitte M. Putzer. Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B26.