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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 Article has an altmetric score of 2

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

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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 7

Measurement of E2F3A and E2F3B protein stability.

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Measurement of E2F3A and E2F3B protein stability.
(A) Venn diagram illus...
(A) Venn diagram illustrating the overlap of genes that are bound by E2F3A and E2F3B in the promoter region (±2 kb from the TSS). (B) Gene ontology using IPA software showing the estimated contribution of different groups of E2F3A and E2F3B target genes identified in A to HCC-related functions. Bars indicate the Benjamini-Hochberg adjusted P value; the threshold of P = 0.05 is shown. (C) Immunoblot showing the stable overexpression of MYC-tagged E2F3A or E2F3B in MEFs. Antibodies against the MYC epitope were used to detect tagged proteins, and tubulin was used as a loading control. (D) Cycloheximide time course of MEFs stably overexpressing MYC-tagged E2F3A or E2F3B. Protein levels of E2F3A and E3F3B were measured by Western blotting at the indicated time points following cycloheximide treatment (10 μg/ml). Antibodies against the MYC epitope were used to detect tagged proteins. Tubulin was used as a loading control. Quantification of E2F3A and E2F3B protein relative to time = 0 is indicated below each blot. (E) Quantification of E2F3A and E2F3B protein stability as described in D. Means of 3 experiments are shown. Error bars indicate ± SEM. t1/2 is the estimated half-life of the protein. The stability of E2F3A and E2F3B was found to be different by Wilcoxon signed rank test using the average of each time point (P < 0.05).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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