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

Min Hwa Shin, Yunlong He, Eryney Marrogi, Sajida Piperdi, Ling Ren, Chand Khanna, Richard Gorlick, Chengyu Liu, Jing Huang

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Article numbere1005884
JournalPLoS Genetics
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2016

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ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Shin, M. H., He, Y., Marrogi, E., Piperdi, S., Ren, L., Khanna, C., Gorlick, R., Liu, C., & Huang, J. (2016). A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells. PLoS Genetics, 12(2), [e1005884]. https://doi.org/10.1371/journal.pgen.1005884