E2f8 mediates tumor suppression in postnatal liver development
Lindsey N. Kent, … , Alain de Bruin, Gustavo Leone
Lindsey N. Kent, … , Alain de Bruin, Gustavo Leone
Published July 25, 2016
Citation Information: J Clin Invest. 2016;126(8):2955-2969. https://doi.org/10.1172/JCI85506.
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E2f8 mediates tumor suppression in postnatal liver development

Abstract

E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.

Authors

Lindsey N. Kent, Jessica B. Rakijas, Shusil K. Pandit, Bart Westendorp, Hui-Zi Chen, Justin T. Huntington, Xing Tang, Sooin Bae, Arunima Srivastava, Shantibhusan Senapati, Christopher Koivisto, Chelsea K. Martin, Maria C. Cuitino, Miguel Perez, Julian M. Clouse, Veda Chokshi, Neelam Shinde, Raleigh Kladney, Daokun Sun, Antonio Perez-Castro, Ramadhan B. Matondo, Sathidpak Nantasanti, Michal Mokry, Kun Huang, Raghu Machiraju, Soledad Fernandez, Thomas J. Rosol, Vincenzo Coppola, Kamal S. Pohar, James M. Pipas, Carl R. Schmidt, Alain de Bruin, Gustavo Leone

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Figure 3

E2F8 tumor suppressor function during early postnatal development.

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E2F8 tumor suppressor function during early postnatal development. (A) D...
(A) Diagram illustrating the temporal deletion of E2f8 using Alb-CreERT2 E2f8fl/fl (Cre–) and Alb-CreERT2 E2f8fl/fl (Cre+) male littermates were fed tamoxifen chow (Tam) for 7 days, starting at their first and fourth week of life. DEN was administered to all mice at 20 days of age and mice were harvested at 9 months of age. (B) PCR genotyping of liver samples from 9-month-old DEN-treated Cre– and Cre+ male mice. The 8fl (670 bp) and the 8Δ band (500 bp) are noted. (C) Representative pictures of livers (top) and H&E-stained liver sections (below) from 9-month-old DEN treated Cre– and Cre+ male mice. Areas of HCC are outlined by dotted lines. T and N, tumor and normal liver, respectively. Scale bars: 1 cm (top) and 100 μm (bottom). (D) Box plots showing the liver/body wt. of mice from C. Statistical significance was determined using Student’s t tests comparing Cre– and Cre+ groups; *P = 0.007. n, number of mice in each group.