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PLoS Genet. 2016 Feb 29;12(2):e1005884. doi: 10.1371/journal.pgen.1005884. eCollection 2016 Feb.

A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells.

Author information

1
Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
2
Division of Pediatric Hematology-Oncology, The Children's Hospital at Montefiore, Bronx, New York, United States of America.
3
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
4
Transgenic Core Facility, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America.

Abstract

The inactivation of p53 creates a major challenge for inducing apoptosis in cancer cells. An attractive strategy is to identify and subsequently target the survival signals in p53 defective cancer cells. Here we uncover a RUNX2-mediated survival signal in p53 defective cancer cells. The inhibition of this signal induces apoptosis in cancer cells but not non-transformed cells. Using the CRISPR technology, we demonstrate that p53 loss enhances the apoptosis caused by RUNX2 knockdown. Mechanistically, RUNX2 provides the survival signal partially through inducing MYC transcription. Cancer cells have high levels of activating histone marks on the MYC locus and concomitant high MYC expression. RUNX2 knockdown decreases the levels of these histone modifications and the recruitment of the Menin/MLL1 (mixed lineage leukemia 1) complex to the MYC locus. Two inhibitors of the Menin/MLL1 complex induce apoptosis in p53 defective cancer cells. Together, we identify a RUNX2-mediated epigenetic mechanism of the survival of p53 defective cancer cells and provide a proof-of-principle that the inhibition of this epigenetic axis is a promising strategy to kill p53 defective cancer cells.

PMID:
26925584
PMCID:
PMC4771715
DOI:
10.1371/journal.pgen.1005884
[Indexed for MEDLINE]
Free PMC Article

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