Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma
Lindsey N. Kent, … , James M. Pipas, Gustavo Leone
Lindsey N. Kent, … , James M. Pipas, Gustavo Leone
Published January 30, 2017
Citation Information: J Clin Invest. 2017;127(3):830-842. https://doi.org/10.1172/JCI87583.
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Research Article Cell biology Hepatology

Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma

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.

Authors

Lindsey N. Kent, Sooin Bae, Shih-Yin Tsai, Xing Tang, Arunima Srivastava, Christopher Koivisto, Chelsea K. Martin, Elisa Ridolfi, Grace C. Miller, Sarah M. Zorko, Emilia Plevris, Yannis Hadjiyannis, Miguel Perez, Eric Nolan, Raleigh Kladney, Bart Westendorp, Alain de Bruin, Soledad Fernandez, Thomas J. Rosol, Kamal S. Pohar, James M. Pipas, Gustavo Leone

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Figure 2

Ablation of E2f1 or E2f3b, but not E2f3a, decreases HCC severity in mice.

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Ablation of E2f1 or E2f3b, but not E2f3a, decreases HCC severity in mice...
(A) Box plots showing the ratio of liver vs. body weight (liver/body wt.) of 9-month-old WT (E2f+/+) and E2f knockout male mice. Non–DEN-treated cohorts are in white, and DEN-treated are shown in gray. The center lines in boxes represent the median. The box represents the first and third quartiles, and the whiskers represent the highest and lowest values. Outliers are represented by gray dots. (B) Histopathological classification of mice from A. Carc. MF, carcinoma multifocal; Carc. F, carcinoma focal; Aden, adenoma; FCA, focal cellular atypia; NSL, no significant lesions. Fisher’s exact tests with Bonferroni’s correction for multiple tests. ‡P ≤ 0.001, carcinoma (focal/multifocal) vs. E2f+/+. (C) Box plots showing liver/body weight of 14-month-old male mice. Non–DEN-treated cohorts are in white, and DEN-treated are shown in gray. *P = 0.040, 1–/– vs. E2f+/+ liver; Wilcoxon method with Bonferroni’s correction. (D) Histopathological classification of mice from C. Fisher’s exact tests with Bonferroni’s correction. ‡P ≤ 0.003, carcinoma vs. E2f+/+.