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

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

来源：Journal of Clinical Investigation, 2017, 127(3): 830-842.

DOI：10.1172/JCI87583

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.

• 出版日期2017-3-1