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

72 Citations (Scopus)

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

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Neoplastic Stem Cells
Epigenomics
Ovarian Neoplasms
Aldehyde Dehydrogenase
Platinum
Neoplasms
Stem Cells
Phenotype
Carboplatin
DNA
Residual Neoplasm
DNA Methylation
Heterografts
Genes
Cell Differentiation
SGI-110
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, Y., Cardenas, H., Fang, F., Condello, S., Taverna, P., Segar, M., ... 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

Epigenetic targeting of ovarian cancer stem cells. / Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P.; Matei, Daniela.

In: Cancer Research, Vol. 74, No. 17, 01.09.2014, p. 4922-4936.

Research output: Contribution to journalArticle

Wang, Y, Cardenas, H, Fang, F, Condello, S, Taverna, P, Segar, M, Liu, Y, Nephew, KP & Matei, D 2014, 'Epigenetic targeting of ovarian cancer stem cells', Cancer Research, vol. 74, no. 17, pp. 4922-4936. https://doi.org/10.1158/0008-5472.CAN-14-1022
Wang Y, Cardenas H, Fang F, Condello S, Taverna P, Segar M et al. Epigenetic targeting of ovarian cancer stem cells. Cancer Research. 2014 Sep 1;74(17):4922-4936. https://doi.org/10.1158/0008-5472.CAN-14-1022
Wang, Yinu ; Cardenas, Horacio ; Fang, Fang ; Condello, Salvatore ; Taverna, Pietro ; Segar, Matthew ; Liu, Yunlong ; Nephew, Kenneth P. ; Matei, Daniela. / Epigenetic targeting of ovarian cancer stem cells. In: Cancer Research. 2014 ; Vol. 74, No. 17. pp. 4922-4936.
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