Dosage-dependent Copy Number Gains in E2f1 and E2f3 Drive Hepatocellular Carcinoma

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2017 Jan 31

PMID 28134624

Citations 66

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

Affiliations

Soon will be listed here.

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.

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