Epigenetic silencing of tumor suppressor genes by aberrant DNA methylation and histone modifications at their promoter regions plays an important role in the initiation and progression of cancer. The therapeutic effect of the widely used epigenetic drugs, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, remains unsatisfactory. One important underlying factor in the ineffectiveness of these drugs is that their actions lack specificity.
To investigate whether oocyte extract can be used for epigenetic re-programming of cancer cells, H460 human lung cancer cells were reversibly permeabilized and incubated with bovine oocyte extract.
Bisulfite sequencing showed that bovine oocyte extract induced significant demethylation at hypermethylated promoter CpG islands of the tumor suppressor genes RUNX3 and CDH1; however, the DNA methylation levels of repetitive sequences were not affected. Chromatin immunoprecipitation showed that bovine oocyte extract significantly reduced transcriptionally repressive histone modifications and increased transcriptionally activating histone modifications at the promoter regions of RUNX3 and CDH1. Bovine oocyte extract reactivated the expression of RUNX3 and CDH1 at both the messenger RNA and the protein levels without up-regulating the transcription of pluripotency-associated genes. At the functional level, anchorage-independent proliferation, migration and invasion of H460 cells was strongly inhibited.
These results demonstrate that bovine oocyte extract reactivates epigenetically silenced tumor suppressor genes by remodeling the epigenetic modifications at their promoter regions. Bovine oocyte extract may provide a useful tool for investigating epigenetic mechanisms in cancer and a valuable source for developing novel safe therapeutic approaches that target epigenetic alterations.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Cytotherapy
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- An overview of epigenetics and chemoprevention.FEBS Lett. 2011; 585: 2129-2136
- Epigenetics in cancer.Carcinogenesis. 2010; 31: 27-36
- Epigenetic therapy of cancer: past, present and future.Nat Rev Drug Discov. 2006; 5: 37-50
- Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2′-deoxycytidine results in increased tumorigenicity.PloS One. 2009; 4: e8340
- Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.Int J Cancer. 2009; 124: 81-87
- Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells.PloS One. 2012; 7: e45045
- Histone deacetylase inhibitors stimulate dedifferentiation of human breast cancer cells through WNT/β-catenin signaling.Stem Cells. 2012; 30: 2366-2377
- Active DNA demethylation: many roads lead to Rome.Nat Rev Mol Cell Biol. 2010; 11: 607-620
- Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos.Proc Natl Acad Sci U S A. 2001; 98: 13734-13738
- Epigenetic marks in somatic chromatin are remodelled to resemble pluripotent nuclei by amphibian oocyte extracts.Epigenetics. 2009; 4: 194-202
- Synergic reprogramming of mammalian cells by combined exposure to mitotic Xenopus egg extracts and transcription factors.Proc Natl Acad Sci U S A. 2011; 108: 17331-17336
- Cell-free extracts from mammalian oocytes partially induce nuclear reprogramming in somatic cells.Biol Reprod. 2009; 80: 935-943
- Identification and characterization of an oocyte factor required for development of porcine nuclear transfer embryos.Proc Natl Acad Sci U S A. 2011; 108: 7040-7045
- Remodeling of ribosomal genes in somatic cells by Xenopus egg extract.Biochem Biophys Res Commun. 2011; 412: 487-493
- Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer.Biochem Biophys Res Commun. 2004; 314: 223-228
- Multifactorial regulation of E-cadherin expression: an integrative study.Mol Cancer Ther. 2010; 9: 1-16
- Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming.J Biol Chem. 2004; 279: 52353-52360
- Mutagenicity of the cytidine analog zebularine in Escherichia coli.DNA Repair. 2004; 3: 155-161
- Therapeutic approaches to target cancer stem cells.Cancers. 2011; 3: 3331-3352
- Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state.Cancer Res. 2006; 66: 3541-3549
- Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer.Nat Genet. 1999; 21: 103-107
- Modest reactivation of the mutant FMR1 gene by valproic acid is accompanied by histone modifications but not DNA demethylation.Pharmacogenet Genomics. 2008; 18: 738-741
- Clinical studies of histone deacetylase inhibitors.Clin Cancer Res. 2009; 15: 3958-3969
- RUNX3 is multifunctional in carcinogenesis of multiple solid tumors.Oncogene. 2010; 29: 2605-2615
- MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.Nature. 2004; 431: 1112-1117
- E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers.EMBO J. 1995; 14: 6107-6115
- The cell-cell adhesion molecule E-cadherin.Cell Mol Life Sci. 2008; 65: 3756-3788
- microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs.RNA. 2011; 17: 1529-1543
Published online: June 24, 2013
Accepted: May 5, 2013
Received: March 10, 2013
© 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.