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Mol Cancer Res. 2016 Feb;14(2):163-172. doi: 10.1158/1541-7786.MCR-15-0313. Epub 2015 Dec 9.

Integrative Analysis Reveals the Transcriptional Collaboration between EZH2 and E2F1 in the Regulation of Cancer-Related Gene Expression.

Xu H#1,2, Xu K#1,2,3, He HH1,2,3, Zang C1,2, Chen CH1,2, Chen Y1,2, Qin Q2, Wang S2, Wang C2, Hu S2, Li F2, Long H2, Brown M2,3, Liu XS1,2,4.

Author information

1
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
2
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
4
School of Life Science and Technology, Tongji University, Shanghai 02138, China.
#
Contributed equally

Abstract

Overexpression of EZH2 is frequently linked to the advanced and metastatic stage of cancers. The mechanisms of its oncogenic function can be context specific, and may vary depending on the protein complexes that EZH2 interacts with. To identify novel transcriptional collaborators of EZH2 in cancers, a computational approach was developed that integrates protein-DNA binding data, cell perturbation gene expression data, and compendiums of tumor expression profiles. This holistic approach identified E2F1, a known mediator of the Rb tumor suppressor, as a transcriptional collaborator of EZH2 in castration-resistant prostate cancer. Subsequent analysis and experimental validation found EZH2 and E2F1 cobind to a subset of chromatin sites lacking H3K27 trimethylation, and activate genes that are critical for prostate cancer progression. The collaboration of EZH2 and E2F1 in transcriptional regulation is also observed in diffuse large B-cell lymphoma cell lines, where activation of the transcriptional network is concordant with the cellular response to the EZH2 inhibitor.

IMPLICATIONS:

The direct collaboration between EZH2 and Rb/E2F1 pathway provides an innovative mechanism underlying the cascade of tumor progression, and lays the foundation for the development of new anticancer targets/strategies.

PMID:
26659825
PMCID:
PMC4828727
DOI:
10.1158/1541-7786.MCR-15-0313
[Indexed for MEDLINE]
Free PMC Article

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