Epigenetics, miRNAs & nutraceuticals

New Italian paper below [1].  

Epigenetic changes are changes that occur above the genetic level.  As such, protective genes may be silenced, but they are not altered.  In theory, epigenetic changes can be reversed & the genes allowed to function.

microRNAs are involved in epigenetic silencing of RNAs & regulation of gene expression.

Nutrachemicals in the paper refers to "nutritional and natural agents", particularly polyphenols. 

I don't have access to the full text, but some examples follow, & a list of potential polyphenols appear at the end.  For those who have given up on supplements, it is important to note that some of the signaling pathways affected by polyphenols are involved in drug resistance.

[2]  (2010) used the polyphenol EGCG from green tea.

"We ... observed a significant down-regulation of androgen-regulated miRNA-21 and up-regulation of a tumor suppressor, miRNA-330, in tumors of mice treated with EGCG."

[3]  (2015)  "Epigenetic potential of resveratrol and analogs."  "Here, we provide a concise summary of our results on epigenetic mechanisms of resveratrol and analogs mediated through regulation of chromatin modifier metastasis-associated protein 1 (MTA1) and microRNAs (miRNAs), and highlight the anticancer effects of these compounds in preclinical models of prostate cancer."

[4]  (2015)  Curcumin & miRNA-21.

"Recent studies have revealed that curcumin may affect cancer initiation and progression through regulating microRNAs (miRs). In this review, we focus on the roles of microRNA-21 (miR-21) in the anti-cancer effects of curcumin and regulatory mechanisms for the effects of curcumin on miR-21. MiR-21 mediates various effects of curcumin on cancer cells including proliferation, apoptosis, metastasis and anti-cancer drug resistance."

Some background.

[5]  "MicroRNAs (miRNA) are noncoding RNAs that post-transcriptionally regulate gene expression. Their altered expression and function have been observed in most urologic cancers. MiRNAs represent potential disease biomarkers and novel therapeutic targets."  "More than 40 miRNAs have been implicated in urologic cancer and many target common carcinogenic pathways."

[6]  "MicroRNAs and phytochemicals

Polyphenols

Curcumin

Curcumin, a bioactive ingredient in turmeric, possesses anti-inflammatory, antioxidant, and anti-carcinogenic properties, although such effects are not always realized in vivo [158, 159]. An initial study evaluated miRNA profiles in curcumin-treated pancreatic cancer cells, with evidence for upregulation of 11 miRNAs and downregulation of 18 miRNAs. MiR-22 was upregulated upon curcumin treatment, and the predicted targets were ERα and transcription factor Sp1. MiR-196, an oncogenic miRNA in gastric cancers, was significantly downregulated after curcumin treatment [160]. Due to the low bioavailability of curcumin in vivo, a synthetic analogue (CDF- diflourinated-curcumin) was evaluated in a chemopreventive pancreatic cancer model [112]. Curcumin and its CDF analog, alone or in combination, attenuated expression of miR-200 and miR-21 leading to induction of tumor suppressor PTEN. The CDF analog inhibited sphere forming ability (pancreatospheres) by attenuating cancer stem cell markers and other signaling molecules, via changes in miR-21 and miR-200. These findings suggested a role for certain miRNAs in tumor recurrence in pancreatic cancer, and the effectiveness of the CDF analog as an alternative therapeutic strategy to curcumin parent compound [161]. In a recent study of curcumin and multi-drug resistance, alterations were detected in 342 miRNAs [162]. Significant changes (> 2.5 fold) in various oncogenic and tumor suppressor miRNAs were reported after curcumin treatment. A key target was miR-186*, which promoted apoptosis in cancer cells. Overall, these studies provided support for the idea that diet-induced miRNAs play a role in overcoming drug resistance in cancers.

Resveratrol

Resveratrol is a chemopreventive agent from grapes, mulberries, wine, and peanuts. Effects of resveratrol on colon cancer cells were examined by Tili et al. [163]. Several “signature” miRNAs for colon cancer such as miR-21, miR- 196a, miR- 25, miR-17, and miR-92a-2 were significantly downregulated by resveratrol. Simultaneously, miR-663-mediated regulation of Dicer, PDCD4, PTEN, and TGFβ signaling through the SMAD promoter was observed. This study provided the first insights into resveratrol-mediated miR-663 regulation in colon cancer cells. A resveratrol-induced, miR-663-dependent effect was observed in monocytic cells used to evaluate adaptive and innate immune responses [164]. MiR-663 was reported to target Activator Protein-1 (AP-1) through the Jun signaling pathway. Interestingly, resveratrol also impaired the upregulation of oncogenic miR-155 in a miR-663-dependent manner.

Catechins

Chemopreventive effects of epigallocatechin-3-gallate (EGCG) and other tea catechins have been described in preclinical models for all major sites of cancer development, including colon, prostate, breast, lung, liver, and skin. Mechanistically, EGCG and related catechins target various cancer signaling pathways in a pleiotropic manner; however, clinical efficacy is less clear [165–168]. Recently, miRNAs were included among the molecular targets of EGCG. In human hepatocellular carcinoma cells, one of the 13 miRNAs that was upregulated on EGCG treatment was miR-16, a tumor suppressor miRNA that mediated apoptosis via downregulation of Bcl-2. This mechanistic target was identified based on transfection studies [169]. Further work is needed to elucidate the detailed miRNA “target map” following treatment with EGCG and, equally importantly, by potential chemopreventive metabolites such as the glucuronide and O-methylated forms which constitute the major fractions found in plasma after oral ingestion.

Ellagitannin

Ellagitannins are polymeric polyphenols found in abundance in strawberries, raspberries, almonds, walnuts, and various other fruits and nuts. They were initially characterized for their anti-oxidant and free radical scavenging activity. Anti-inflammatory, anti-tumor promoting, anti-proliferative, and apoptosis-inducing properties also have been identified [170]. A plant grown in Japan and China, Balanophora Japonica MAKINO, contains 1,3-di-O-galloyl-4,6-(s)-HHDP-b-D-glucopyranose. This ellagitannin was examined for anti-proliferative effects in human liver cancer cells, along with profiling of miRNAs [171]. Using a dose- and time-dependent strategy, 17 miRNAs were found to be upregulated and 8 miRNAs were downregulated following treatment of HepG2 cells, including let-7 family members, miR-370, miR-373, and miR-526b. Prediction software and functional analyses identified likely targets with roles in cell proliferation and differentiation; however, the precise mechanisms await further study.

Isoflavones

Soy isoflavones, including genistein, daidzein, and glycitein, have been implicated in anti-carcinogenic mechanisms, via the modulation of estrogen receptor binding in target tissues. Genistein is currently undergoing clinical trials for chemopreventive and therapeutic effects in breast, prostate, bladder, and kidney cancers [172]. Li et al. [103] examined whether isoflavones altered miRNA profiles in pancreatic cancer, and noted a differential effect in gemcitabine-resistant versus gemcitabine-sensitive cancer cells. For example, miRNAs belonging to miR-200 and let-7 families were downregulated in gemcitabine-resistant cells versus gemcitabine-sensitive cells. However, isoflavone treatment increased both miR-200 and let-7 family miRNAs by modulating EMT transcription factors, such as vimentin, slug, and ZEB1. Genistein also upregulated miR-146a in pancreatic cancer cells, inhibiting their invasive potential by downregulating EGFR, NFκB, IRAK-1, and MTA-2 [173].

Another study [174] examined minichromosome maintenance (MCM) genes involved in DNA replication, which are commonly dysregulated in cancer cells. In prostate cancer cells treated with genistein, MCM2 was downregulated by miR-1296. Genistein induced the expression of miR-1296 by up to five-fold, along with cell cycle arrest in S-phase. Chemopreventive effects of genistein on the temporal changes during ovarian cancer progression were assessed using microarray analyses [175]. This was a descriptive study that focused on significant alterations in miRNAs, and awaits further validation of potential targets. Genistein also was investigated in other cancer models, such as human uveal melanoma cells [176]; using both in vitro and in vivo models, miR-27a was found to be downregulated with concomitant upregulation of its target gene, ZBTB10.

Indoles

Cruciferous/Brassica vegetables have received considerable attention due to the chemopreventive properties of the whole food or isolated compounds, such as sulforaphane and indole-3-carbinol (I3C) [177]. Upon ingestion, I3C undergoes acid condensation reactions in the stomach producing a number of oligomers including dimers, trimers, and tetramers. The major compound found in vivo in human plasma is 3,3′-diindolylmethane (DIM) which has been examined for chemoprotective mechanisms in breast, colon, prostate, pancreatic and cervical cancer [178]. In a well-designed study by Izzotti et al. [179], altered miRNA profiles in lung tissue were observed in rats exposed to environmental cigarette smoke. Restoration of miRNAs targeting p53 functions (miR-34b), TGF-β expression (miR-26a), ERBB2 activation (miR-125a), and angiogenesis (miR-10a) was recorded on treatment with five dietary agents, including I3C. Also, as discussed in the studies by Li et al. [103, 173], along with soy isoflavones, DIM influenced EMT via differentially expressed miRNAs in pancreatic cancer cells. Based on these initial reports with I3C and DIM in cancer models, miRNAs appear to be promising molecular targets of dietary indoles, awaiting further mechanistic validation.

Isothiocyanates

Isothiocyanates derived from cruciferous vegetables modulate carcinogen metabolism in different tissues, but likely exert numerous other chemoprotective mechanisms [177, 180]. The effect of phenethyl isothiocyanate (PEITC) on miRNA alterations induced by smoking in rat lung tissue was evaluated by Izzoti et al. [181]. Of the five dietary agents tested, PEITC intervention alone, or in combination with I3C, was the most effective in restoring miRNAs downregulated by exposure to cigarette smoke. Major PEITC-induced miRNA targets were miR-192 (Ras activation); let-7a, let-7c (cell proliferation, angiogenesis, Ras activation); miR-146 (NFκB activation); miR-123, miR-222, (angiogenesis, cell proliferation), and miR-99b (apoptosis). In another study by the same group, miRNA alterations upon exposure to cigarette smoke were investigated in mouse lung and liver tissues [182]. PEITC-induced changes in miRNA expression profiles were more robust in mouse liver (significant > 2-fold downregulation of 9 oncogenic miRNAs and upregulation of 3 tumor suppressor miRNAs) as compared to lung tissue. It would be interesting to evaluate the effect of other dietary isothiocyanates on miRNA expression profiles in cancer models.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/271...

Anticancer Agents Med Chem. 2016 Apr 24. [Epub ahead of print]

Epigenetic and miRNAs dysregulation in prostate cancer: the role of nutraceuticals.

Bosutti A, Zanconati F, Grassi G, Dapas B, Passamonti S, Scaggiante B1.

Author information

1Dept. of Life Sciences Via Giorgeri, 1 University of Trieste 34127 Trieste Italy. bscaggiante@units.it.

Abstract

The control of cancer onset and progression is recognized to benefit from specific molecular targeting. MiRNAs are increasingly being implicated in prostate cancer, and the evidence suggests they are possible targets for molecular therapy and diagnosis. In cancer cells, growing attention has been dedicated to novel molecular mechanisms linking the epigenetic scenario to miRNA dysregulation. Currently, the rising evidence shows that nutritional and natural agents, the so-called nutraceuticals, could modulate miRNAs expression, and, as a consequence, might influence cellular responses in health or diseases conditions, including cancer. Among dietary components, plant-derived polyphenols are receiving wide interest, either for their anti-aging and anti-oxidant properties, or for their more general "cell-protective" effects. Above all, their role in preventing the occurrence/recurrence of cancer and, in particular, their potentiality in nutritional intervention for modulating the functions of miRNAs and the epigenetic mechanisms, is still under active debate. This review is focused on the more recent highlights of the impact of miRNAs dysregulation on the onset and progression of prostate cancer, their interplay with epigenetic control and their modulation by natural agents.

PMID: 27109021 [PubMed - as supplied by publisher]

[2] ncbi.nlm.nih.gov/pmc/articl...

[3] ncbi.nlm.nih.gov/pubmed/262...

[4] ncbi.nlm.nih.gov/pubmed/267...

[5] ncbi.nlm.nih.gov/pubmed/212...

[6] ncbi.nlm.nih.gov/pmc/articl...

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  • Thanks for information. Had radiation w/ hormone therapy after 01/14 dx w/ high risk(Gleason 8,PSA 10).  Went vegan, drink green tea, 8 servings high antioxidant  vegetables, tofu & soymilk daily. Lost 15 lbs.  PSA has been > 0.1 since. Good luck