Faculty Collaboration Database

E2f8 mediates tumor suppression in postnatal liver development. J Clin Invest 2016 Aug 01;126(8):2955-69

Date

07/28/2016

Pubmed ID

27454291

Pubmed Central ID

PMC4966321

DOI

10.1172/JCI85506

Scopus ID

2-s2.0-84987814871 (requires institutional sign-in at Scopus site)   67 Citations

Abstract

E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.

Author List

Kent LN, Rakijas JB, Pandit SK, Westendorp B, Chen HZ, Huntington JT, Tang X, Bae S, Srivastava A, Senapati S, Koivisto C, Martin CK, Cuitino MC, Perez M, Clouse JM, Chokshi V, Shinde N, Kladney R, Sun D, Perez-Castro A, Matondo RB, Nantasanti S, Mokry M, Huang K, Machiraju R, Fernandez S, Rosol TJ, Coppola V, Pohar KS, Pipas JM, Schmidt CR, de Bruin A, Leone G

Authors

Hui-Zi Chen MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Biopsy
Carcinoma, Hepatocellular
Cell Proliferation
Cell Survival
DNA
E2F7 Transcription Factor
Female
Gene Deletion
Genotype
Hepatocytes
Humans
Liver
Liver Neoplasms
Male
Mice
Oligonucleotide Array Sequence Analysis
Protein Binding
Protein Domains
Repressor Proteins
Sequence Analysis, RNA
Signal Transduction