Pterostilbene and Resveratrol suppress breast cancer tumor growth by epigenetic reprogramming

Epigenetics is about changes happening in organisms caused by modification of gene expression rather than changes in the genetic code itself. More simple it is about biological mechanisms that will switch genes on and off. Epigenetics is believed to play a role in aging but also in diseases. There are 3 main mechanisms that alter the gene expression: DNA methylation, histone modifications, and non-coding RNA mechanisms.

DNA methylation is considered to be the gate-keeper of gene expression providing stable long-term regulation. At the same time, DNA methylation has attracted a significant amount of attention for the prevention and treatment of different illnesses due to the reversibility of epigenetic states. Hypermethylation of tumor suppressor genes linked to transcriptional silencing (=switching them off), and recently reported promoter hypomethylation linked to activation of oncogenes (= a gene that in certain circumstances can transform a cell into a tumor cell) and prometastatic (= metastasis promoting) genes have been shown to play a role in cancer initiation and progression.

The researchers in this study noted that breast cancer has been associated not only with hypermethylation of tumor suppressor genes but also with hypomethylation of oncogenes and pro-metastatic genes. For instance, re-methylation of hypomethylated promoter of uPA, a gene inducing metastatic cell behaviour, was shown to block breast cancer growth and metastasis. They also noted that a number of signaling pathways have been implicated in the development and progression of breast cancer and noteworthy among those is NOTCH signaling. The NOTCH pathway regulates cell proliferation, survival, differentiation, cell-cell communication, angiogenesis and many other processes essential for tumorigenic potential.

This all suggests that there is a need for novel agents that remodel the DNA methylation states to support the suppressing of cancer. Naturally derived compounds that switch cancerous to normal phenotype at minimally toxic doses would be excellent candidates for subtle changes in the DNA methylation profiles. Although limited, there are pieces of evidence demonstrating that bioactive compounds found in food and herbs can modulate gene expression by targeting DNA methylation. Specifically, resveratrol (RSV) and pterostilbene (PTS), have shown in rat models an ability to make changes in the epigenome.

The researchers in this study investigated the role of RSV and PTS in remodeling the DNA methylation patterns associated with breast cancer and how these epigenetic effects correlate with the anti-cancer action of the compounds. The reseacrhers did the testing in-vitro using two human breast cancer cell lines, lowly invasive MCF10CA1h and highly invasive MCF10CA1a.

The analysis revealed that the treatment with RSV and PTS resulted in a dose- and time-dependent inhibition in cell proliferative and invasive properties in breast cancer cells. It also revealed that treatment with RSV and PTS does indeed alter DNA methylation patterns in breast cancer cells. On average 75% of differentially methylated genes (=difference between tumor tissue and healthy tissue) have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. Among observed effects in response to RSV and PTS the MAML2, a co-activator of NOTCH targets, is transcriptionally silenced possibly explaining the downregulation of NOTCH target genes. NOTCH signaling is, as mentioned before, a pathway implicated in the development and progression of breast cancer.

The results of this in-vitro study demonstrates that resveratrol and pterostilbene inhibits breast cancer development via epigenetic mechanisms and therefore provides a novel insight into the possible effectiveness of epigenetic-targeting strategies as an effective anti-cancer approach.

 

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