ArticlePloS one2012
Reactivation of the tumour suppressor RASSF1A in breast cancer by simultaneous targeting of DNA and E2F1 methylation.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 29 citations in OpenAlex.
- Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy.Cell death & disease · 2023Article
- Effects of a Semisynthetic Catechin on Phosphatidylglycerol Membranes: A Mixed Experimental and Simulation Study.Molecules (Basel, Switzerland) · 2023Article
- 3,4,5-Trimethoxybenzoate of Catechin, an Anticarcinogenic Semisynthetic Catechin, Modulates the Physical Properties of Anionic Phospholipid Membranes.Molecules (Basel, Switzerland) · 2022Article
- RASSF1C oncogene elicits amoeboid invasion, cancer stemness, and extracellular vesicle release via a SRC/Rho axis.The EMBO journal · 2021Article
- RASSF1A is required for the maintenance of nuclear actin levels.The EMBO journal · 2019Article
- Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells.Pharmacological research · 2016Article
- Article
- RASSF1A Site-Specific Methylation Hotspots in Cancer and Correlation with RASSF1C and MOAP-1.Cancers · 2016Article
- Targeting the epigenetics of the DNA damage response in breast cancer.Cell death & disease · 2016Article
- Differential methylation of the promoter and first exon of the RASSF1A gene in hepatocarcinogenesis.Hepatology research : the official journal of the Japan Society of Hepatology · 2015Article
- Targeting the epigenetic machinery of cancer cells.Oncogene · 2015Review
- ABCB4 is frequently epigenetically silenced in human cancers and inhibits tumor growth.Scientific reports · 2014Article
- Promoting E2F1-mediated apoptosis in oestrogen receptor-α-negative breast cancer cells.BMC cancer · 2014Article
- The functional diversity of protein lysine methylation.Molecular systems biology · 2014Review
- Epigenetic effects of green tea polyphenols in cancer.Epigenomics · 2013Review
- Factors influencing the antifolate activity of synthetic tea-derived catechins.Molecules (Basel, Switzerland) · 2013Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTumour suppressor genes are often transcriptionally silenced by promoter hypermethylation, and recent research has implicated alterations in chromatin structure as the mechanistic basis for this repression. In addition to DNA methylation, other epigenetic post-translational modifications that modulate the stability and binding of specific transcription factors to gene promoters have emerged as important mechanisms for controlling gene expression. The aim of this study was to analyse the implications of these mechanisms and their molecular connections in the reactivation of RASSF1A in breast cancer.
methodsCompounds that modulate the intracellular concentration of adenosine, such as dipyridamole (DIPY), greatly increase the antiproliferative effects of 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin (TMCG), a synthetic antifolate derived from the structure of tea catechins. Quantitative real-time PCR arrays and MALDI-TOF mass spectrometry indicated that this combination (TMCG/DIPY) induced apoptosis in breast cancer cells by modulating the methylation levels of DNA and proteins (such as E2F1), respectively. Chromatin immunoprecipitation (ChIP) assays were employed to confirm that this combination induced chromatin remodelling of the RASSF1A promoter and increased the occupancy of E2F1 at the promoter of this tumour suppressor gene.
resultsThe TMCG/DIPY combination acted as an epigenetic treatment that reactivated RASSF1A expression and induced apoptosis in breast cancer cells. In addition to modulating DNA methylation and chromatin remodelling, this combination also induced demethylation of the E2F1 transcription factor. The ChIP assay showed enhancement of E2F1 occupancy at the unmethylated RASSF1A promoter after TMCG/DIPY treatment. Interestingly, inhibition of E2F1 demethylation using an irreversible inhibitor of lysine-specific demethylase 1 reduced both TMCG/DIPY-mediated RASSF1A expression and apoptosis in MDA-MB-231 cells, suggesting that DNA and protein demethylation may act together to control these molecular and cellular processes. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that simultaneous targeting of DNA and E2F1 methylation is an effective epigenetic treatment that reactivates RASSF1A expression and induces apoptosis in breast cancer cells.
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