Dietary stilbenes as modulators of specific miRNAs in prostate cancer

Abstract

Accumulated experimental data have suggested that natural plant products may be effective miRNA-modulating chemopreventive and therapeutic agents. Dietary polyphenols such as flavonoids, stilbenes, and lignans, among others, have been intensively studied for their miRNA-mediated cardioprotective, antioxidant, anti-inflammatory and anticancer properties. The aim of this review is to outline known stilbene-regulated miRNAs in cancer, with a special focus on the interplay between various miRNAs and MTA1 signaling in prostate cancer. MTA1 is an epigenetic reader and an oncogenic transcription factor that is overexpressed in advanced prostate cancer and metastasis. Not surprisingly, miRNAs that are linked to MTA1 affect cancer progression and the metastatic potential of cells. Studies led to the identification of MTA1-associated pro-oncogenic miRNAs, which are regulated by stilbenes such as resveratrol and pterostilbene. Specifically, it has been shown that inhibition of the activity of the MTA1 regulated oncogenic miR-17 family of miRNAs, miR-22, and miR-34a by stilbenes leads to inhibition of prostatic hyperplasia and tumor progression in mice and reduction of proliferation, survival and invasion of prostate cancer cells in vitro. Taken together, these findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.

Keywords: MTA1; active surveillance; biomarkers; chemoprevention; interception; miRNAs; prostate cancer; stilbenes.

FIGURE 1

Chemical structures of dietary stilbenes: Resveratrol, trans-3, 4′, 5-trihydroxystilbene, MW: 228.24 g/mol; Pterostilbene, trans-3,5-dimethoxy-4′-hydroxystilbene, MW: 256.30 g/mol; Piceatannol, trans-3,5,3′4′-tetrahydroxystilbene, MW: 244.24 g/mol; Piceid, trans-resveratrol-3-O-glucoside, MW: 390.39 g/mol; Astringin, trans-piceatannol-3-β-D-glucuronide, MW: 406.38 g/mol; ε-Viniferin, trans-epsilon-resveratrol dimer, MW: 454.50 g/mol; Pallidol, tetracyclic homodimer resveratrol, MW: 454.48 g/mol; Gnetin C, dimer resveratrol, MW: 454.48 g/mol.

FIGURE 2

MiR-mediated biological effects of dietary stilbenes in cancer. Stilbenes from dietary sources such as grapes, blueberries, peanuts, and passion fruits modulate expression of miRNAs involved in promoting cell cycle arrest and apoptosis and inhibiting inflammation, survival pathways, cancer drug resistance and recurrence, invasion and metastasis as well as reducing cancer stem cell population. The stilbene-regulated miRNAs in prostate cancer are shown in red.

FIGURE 3

Effects of dietary stilbenes on the MTA1 signaling pathways including miRNAs. The MTA1/HDAC1,2 signaling is triggered by prostate cancer progression and involves deacetylation of some tumor suppressor (TS) proteins (p53 and PTEN), transcription of oncogenes, and activation of oncogenic miRNAs. These cascades can be inhibited by the dietary stilbenes accumulated in grapes, blueberries and melinjo berries.