Abstract
Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.
Highlights
The E2F family of transcription factors consists of 8 members that can be organized into 3 subcategories based on function and expression patterns during the cell cycle: activators (E2F13), canonical repressors (E2F4–6), and atypical repressors (E2F7 and E2F8)
To explore whether altered E2F signaling may be directly related to development of human cancer, we queried The Cancer Genome Atlas (TCGA; https://tcga-data.nci.nih.gov/docs/publications/tcga/) and Catalogue of Somatic Mutations in Cancer (COSMIC; http:// cancer.sanger.ac.uk/cosmic) databases for genetic and epigenetic alterations in E2F family members
Using a series of E2F alleles to finely tune E2F transcriptional output, we show that increasing output by gains in E2f1 and E2f3b gene-copy numbers leads to hepatocellular carcinoma (HCC) development in mice
Summary
The E2F family of transcription factors consists of 8 members that can be organized into 3 subcategories based on function and expression patterns during the cell cycle: activators (E2F13), canonical repressors (E2F4–6), and atypical repressors (E2F7 and E2F8). To explore a possible role for E2Fs in human cancer, we queried recently generated public databases for genetic alterations in E2F family members This analysis revealed very modest but significant (P < 0.001) increases in E2F1 and E2F3 gene dosage in tumors from advanced HCC patients (Figure 1A). We used a series of loss- and gain-of-function alleles to modulate the levels of E2F1, E2F3A, and E2F3B expression in mice and evaluated their role in cancer This analysis shows that copy number gains in E2f1 or E2f3b led to increased E2F output and a striking incidence of spontaneous HCC without affecting development at any stage, from fetal to adult.
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