Epigenetic targeting of ovarian cancer stem cells

Yinu Wang, Horacio Cardenas, Fang Fang, Salvatore Condello, Pietro Taverna, Matthew Segar, Yunlong Liu, Kenneth P. Nephew, Daniela Matei

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH+ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH+cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.

Original languageEnglish (US)
Pages (from-to)4922-4936
Number of pages15
JournalCancer Research
Volume74
Issue number17
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, Y., Cardenas, H., Fang, F., Condello, S., Taverna, P., Segar, M., Liu, Y., Nephew, K. P., & Matei, D. (2014). Epigenetic targeting of ovarian cancer stem cells. Cancer Research, 74(17), 4922-4936. https://doi.org/10.1158/0008-5472.CAN-14-1022