The role of polyphenols in the epigenetic regulation of tumor

Abstract

Polifenoli su sekundarni biljni metaboliti koji u ljudskom tijelu pokazuju pozitivne učinke na različite bolesti, uključujući i tumore. Tumor nastaje kao posljedica genetskih i epigenetskih promjena, a polifenoli mogu utjecati na inhibiciju razvoja i rasta tumora mijenjajući reverzibilne epigenetske modifikacije. U ovom je radu opisan upravo učinak polifenola na izmjenu aberantnih epigenetskih modifikacija u tumorskih stanica. Polifenoli su se pokazali kao inhibitori DNA metiltransferaze pri čemu sprečavaju metilaciju DNA i omogućavaju transkripcijsku aktivnost. Pokazali su učinak i na modifikacije histona (acetilaciju i metilaciju) gdje aktivacijom ili inhibicijom uključenih enzima (histon acetil- i metil-tranferaze te histon deacetilaze i demetilaze) mogu regulirati stanje kromatina, a preko toga i transkripciju. Treći način regulacije genske ekspresije pokazan je u obliku smanjivanja ili povećavanja razine ekspresije različitih miRNA koje onda utječu na ekspresiju ostalih faktora uključenih u kancerogenezu. Preko ova tri mehanizma omogućena je regulacija transkripcijske aktivnosti što je bitno za izmjenu nepravilnih ekspresija tumor-supresorskih gena i onkogena u tumorskih stanica. Utišavanjem onkogena i reaktivacijom epigenetički utišanih tumor-supresor gena polifenoli inhibiraju rast tumora. Iako daju dobre rezultate u uvjetima in vitro, polifenoli se još uvijek ne mogu koristiti u svrhu terapije zbog nespecifičnog djelovanja na enzime, zbog tkivno specifičnih epigenetskih modifikacija te zbog nedostupnosti u živom organizmu. Ukoliko se riješe ovi problemi, polifenoli predstavljaju budućnost kemoprevencije i terapije tumora.Polyphenols are secondary plant metabolites that show positive effects on various human diseases, including tumors. Tumor appears as a result of genetic and epigenetic changes, and polyphenols can affect the inhibition of tumor growth by altering the reversible epigenetic modification. This paper describes the effect of polyphenols on the aberrant epigenetic modification in tumor cells. Polyphenols have been shown to inhibit DNA methyltransferase which results in inhibition of DNA methylation and activation of transcriptional activity. They also demonstrated the effect on histone modification (acetylation and methylation) where activation or inhibition of involved enzymes (histone acetyl- and methyl-tranferase, histone deacetylase and demethylase) can regulate the chromatin state and with that a transcriptional activity. The third model of regulation of gene expression has been shown to reduce or increase the expression level of different miRNAs, which then influence the expression of other factors involved in carcinogenesis. Through these three mechanisms it is possible to regulate transcriptional activity which is essential for the modification of improper expression of tumorsuppressor genes and oncogenes in tumor cells. By silencing of the oncogenes and the reactivation of epigenetically silenced tumor-suppressor genes polyphenols inhibit tumor growth. Although providing good results in in vitro conditions, polyphenols can not yet be used for therapy because of non-specific action on enzymes, tissue-specific epigenetic modification and lack of bioavailability in the living organism. If these problems are solved, polyphenols represent the future of chemoprevention and tumor therapy