Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer.

Reinhard Dammann,Michelle Woods,Adriana Jiménez,Chamindri Witharana,Miriam Küster,Antje Richter

doi:10.3390/ijms18102160

Abstract

Epigenetic inactivation of tumor suppressor genes (TSG) is a fundamental event in the pathogenesis of human cancer. This silencing is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. One of the most frequently hypermethylated TSG in human cancer is the Ras Association Domain Family 1A (RASSF1A) gene. Aberrant methylation of RASSF1A has been reported in melanoma, sarcoma and carcinoma of different tissues. RASSF1A hypermethylation has been correlated with tumor progression and poor prognosis. Reactivation of epigenetically silenced TSG has been suggested as a therapy in cancer treatment. In particular, natural compounds isolated from herbal extracts have been tested for their capacity to induce RASSF1A in cancer cells, through demethylation. Here, we review the treatment of cancer cells with natural supplements (e.g., methyl donors, vitamins and polyphenols) that have been utilized to revert or prevent the epigenetic silencing of RASSF1A. Moreover, we specify pathways that were involved in RASSF1A reactivation. Several of these compounds (e.g., reseveratol and curcumin) act by inhibiting the activity or expression of DNA methyltransferases and reactive RASSF1A in cancer. Thus natural compounds could serve as important agents in tumor prevention or cancer therapy. However, the exact epigenetic reactivation mechanism is still under investigation.

Highlights

DNA methylation is an important epigenetic modification in mammalians and occurs predominately at CpG dinucleotides in the genome
rat sarcoma genes (Ras) Association Domain Family 1A (RASSF1A) hypermethylation has been correlated cancer, for example with increased progression, advanced staging or metastatic properties [36,47,48]. It has with different hallmarks of advanced pathogenesis of cancer, for example with increased progression, been reported that RASSF1A methylation correlated with a poorer prognosis of cancer patients [42,48]
B12) on the regulation of methylation levels of RASSF1A should be analyzed in further detail and the precise mechanism that modulates this methylation needs to be elucidated

Summary

Introduction

DNA methylation is an important epigenetic modification in mammalians and occurs predominately at CpG dinucleotides in the genome. In the minimal deletion region, others have discovered the Ras Association Domain Family 1 gene (Figure 1) [4,7]. We termed we and others have discovered the Ras Association Domain Family 1 gene (Figure 1) [4,7]. The RASSF1A isoform is transcribed island containing 84 CpG sites, that is often hypermethylated in cancer. SARAH (Sav/Rassf/Hpo) domain phorbol esters and diacylglycerol, which act as tumor promoters is a characteristic coiled-coil structure (Figure 2). It is a small helical module that is important in signalin the regulatory protein WW45 (human homologue of the Drosophila protein Salvador/Sav) and the transduction networks and serves for This domain[11,12,13]. RASSF1C is a 270 aa long protein and encodes a RA/UBQ and a SARAH domain

Hypermethylation of RASSF1A in Human Cancers

Demethylation of RASSF1A by Treatment of Cancer Cells with Cytidine Analogues

Effects of Methyl Donors and Vitamins on RASSF1A Methylation

Impact of Naturally Occurring Polyphenols on RASSF1A Methylation

Effects of Other Natural Compounds on RASSF1A Methylation

Conclusions