Epigenetic Targeting of Ovarian Cancer Stem Cells

Abstract

Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer (OC). 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 cell (OCSC). In this study, we tested the hypothesis that DNA hypomethylating agents may be able to reset OCSC towards 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+ OC 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 re-expression 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 re-programming residual cancer stem-like cells. Further, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.

NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem–like Cells

“…CD133 expression and ALDH activity have been the most consistent markers of ovarian cancer stem cells (31–35). For this reason, we proceeded to measure changes in these markers upon exposure to carboplatin.…”

Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer

“…Female, BALB/c-nu/nu, athymic mice (5-6 weeks old; Harlan) were injected intraperitoneally (IP) with 2 million A2780 cells on day 0. The experimental group (n=3) received weekly carboplatin (Hospira) at 50mg/kg IP starting on day 4 for 3 weeks, while the control group (n=3) received IP PBS, as previously described [23]. Control xenografts were harvested on day 21 from mice not treated with carboplatin.…”

Factors affecting the persistence of drug-induced reprogramming of the cancer methylome

“…To account for differences in initial methylation at each CpG site and amount of methylation lost, we normalized CpGs by their initial and post-treatment DNA methylation levels, such that the degree of demethylation achieved after 6 d of treatment was 100%. DNA methylation changes at later time points (3,6,9, and 27 passages) were used to calculate the fractional recovery of methylation over time in the absence of drug. A self-organizing map (SOM) 21 approach was then used to cluster the CpGs into classes based on their patterns of remethylation.…”

“…1 These drugs have also exhibited activity in solid tumors of the lung in combination with other therapies, including HDAC inhibitors, 2 and are in clinical trials for the treatment of breast 3 and ovarian cancers. 2,[4][5][6] In spite of the considerable use and study of these drugs, the molecular basis of their efficacy remains incompletely understood. As cytidine analogs, DAC and AZA require intracellular conversion to the triphosphate form and incorporation into DNA, where they covalently trap DNA methyltransferase 1 (DNMT1) and lead to its proteasomal degradation.…”

“…10,[15][16][17] These studies implicated several factors in the propensity of given CpG sites to remethylate, including proximity to a transcription start site (TSS), occupancy of RNA Polymerase II (RNAP II), and the presence of certain histone modifications. 10,16 Given the widespread use of these agents and the promising clinical trials underway utilizing DAC or related compounds as a synergistic or sensitizing agents, [4][5][6] it is vital to understand both the extent and stability of DACinduced demethylation given its immediate potential to improve cancer treatment.…”