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

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. PoharJames M. Pipas, Gustavo Leone*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    41 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)830-842
    Number of pages13
    JournalCLIN Journal
    Volume127
    Issue number3
    DOIs
    Publication statusPublished - 1-Mar-2017

    Keywords

    • CELLULAR PROLIFERATION
    • TRANSCRIPTION FACTORS
    • TUMOR SUPPRESSION
    • MOUSE DEVELOPMENT
    • FAMILY-MEMBERS
    • RB
    • CANCER
    • RETINOBLASTOMA
    • PROTEIN
    • ROLES

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