PART 2: Slaying Two Dragons with One Hail of Stones: The Silencing Of Good Genes In Aging And Cancer – And How Polyphenols Can Prevent That

 By James Watson (with editorial help from Vince Giuliano)

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This is the Part 2 of a three-part series of blog entries on the epigenetic’s of cancer and aging and how those two deadly dragons can be seriously slowed down or stopped with the assistance of plant polyphenols. The Part 1 blog entry tells the central story.  It 1. identified similarities in the biological processes and epigenetic’s of cancer and aging, 2.  identified therefore how common strategies might be found that address both cancer and aging.  3.  described the process of Xenohormesis whereby stress response chemicals developed over millions of years in plants that respond to stresses and keep plants healthy can do the same in humans. 4. provided molecular explanations for the “causality” of cancer and aging, 5.  described the processes in cancer and aging of epigenetic silencing of “good” genes and epigenetic activation of “bad” genes, 6. identified a 3 tiered “Pyramid” approach for chemoprevention of aging and cancer, 7. Iidentified the exact interventions involved in each layer of the Pyramid, and 8. Identified how the interventions in the three layers of the Pyramid can be integrated together.  This  Part 2 blog entry is concerned in more detail with the silencing of good genes in aging and cancer and how polyphenols can prevent that.  It lists naturally occurring phytochemicals that inhibit pathways that are known to be unregulated or dysregulated in cancer.  The Part 3 blog entry in this Two-Dragon series is concerned: a. the “unsilencing of bad genes” with sirtuin decline and the harmful results in aging and cancer, and B. providing a master list of drugs and natural compounds for cancer chemoprevention. The Part 2 and Part 3 blog provide a series of appendices to the Part 1 entry, They’re published separately because of blog length considerations and because they are of interest in their own right. 

Part of Aging and Carcinogenesis is due to gene silencing: histone deacetylation, DNA methylation, & chromatin structure Δ: euchromatin è  heterochromatin

We now know that in many cases, gene inactivation is NOT due to a bona fide DNA mutation. Instead, the non-mutated gene can be silenced by an epigenetic mechanism that involves histone deacetylation of the histone proteins surrounding active genes (euchromatin), as well as DNA methylation of a cytosine-rich region of promoter sites (“start location”) on the gene. These cytosine-rich areas are called CpG islands and the cytosine bases can be methylated by the enzyme DNMT.  Thousands of “good genes” must remain in the euchromatin state to allow for gene expression to occur.  When histones are acetylated, transcription factors can reach the DNA because of the “open structure” of the histones.  When the promoter region has a hypomethylated CpG island, the transcription factor can bind to the DNA promoter region.  Transcription factors migrate into the nucleus in response to various cellular signaling pathways.  are “silenced”, they cannot be turned on by cellular signals, even if the gene is not mutated.

The following discussion  explains how gene silencing occurs and then gives some specific examples of gene silencing in aging and cancer.  Further, it goes on to illustrate how specific plant polyphenols can be used to unsilence anti-aging and anti-cancer genes and to silence pro-cancer and pro-aging genes.

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Preventing Histone-based Gene Silencing : Inhibiting histone deacetylation of Lysine 9 on Histone 3 (H3K9) with polyphenols

Aging and cancer exhibit epigenetic silencing of genes that should NOT be silenced. Since only 50% of genes have CpG islands at their promoter sites, DNA methylation is not as common a method of gene silencing as histone-based gene silencing, which can occur for almost all genes.   Histone-based gene silencing is best understood as an imbalance in the equilibrium between histone acetylation (by HAT) and histone deacetylation (by HDACS).  The diagram below illustrates this and how plant polyphenols can inhibit the equilibrium both ways, since some of the polyphenols are both HDAC inhibitors and HAT inhibitors.  HDAC inhibition is a way of preventing gene silencing of euchromatin, whereas HAT inhibition is primarily a way of preventing the activation (expression) of repetitive DNA, which normally is silent.  The transcriptional activation of repetitive DNA is increasingly being studied since it seems to be the consequence of the global decline in DNA methylation that occurs with aging.

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Preventing DNA methylation-based Gene Silencing:  Inhibiting DNA methylation at the CpG islands found in promoter sites with polyphenols

 50% of the promoter sites in human genes have a region that is rich in cytosine bases.  This region is called a “CpG island” and is important in the transcriptional activation of gene expression by transcription factors.  In genes that have a CpG island (50% of the total), gene silencing can occur by methylation of the cytosine bases in the CpG island.  This prevents gene transcription. The enzyme responsible for methylating the cytosines is called DNA methyltransferas.  This is normally the first step in gene silencing and occurs before histone deacetylation. Many natural products including green tea, soybeans, garlic, tomatoes, watercress, curry powder, broccoli, brussel sprouts, cabbage, red grapes, and olives prevent this step in the silencing of “good genes”.  The diagram below illustrates this.

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Other methods of Gene silencing – Histone protein trimethylation and Polycomb protein co-repressor silencing of genes

 There are other mechanisms of epigenetic silencing not covered in this appendix, but should be mentioned for the sake of completeness.  When histone protein tails are deacetylated, the lysine side chains are typically methylated.  Single methyl groups or two methyl groups are associated with down regulation of gene expression but not silencing.  Trimethylation of the histone protein lysine side chains is typically associated with gene silencing.  Polycomb proteins are another form of gene silencing that has been evolutionarily conserved from lower organisms that do not methylate DNA.  The significance of Polycomb protein-based gene silencing is not as clear has the other epigenetic mechanisms described in this Two-Dragon series of entries.  Nevetheless, this Polycomb silencing is important to understand and occasionally comes up in discussions of gene silencing.

Gene Silencing by non-coding RNA – miRNA silencing of tumor suppressor genes and activation of oncogene expression

A third method by which genes can be silences is by the inhibition of messenger RNA (mRNA) by non-coding RNA called miRNA (also called microRNA).  These miRNA bind to mRNA, making them incapable of creating a protein, or increasing the degradation of the mRNA, thereby eliminating the possibility that the mRNA can create a protein. This means that the gene may be transcribed (i.e. a messenger RNA is made), but the mRNA transcript is not “read” and translated into a protein in the ribosomes.  This method of gene silencing can also be used to activate or increase the expression of an oncogene.  Most oncogenes are actually good and necessary genes expressed with normal cellular function, but become overexpressed with cancer.  When this occurs, such a gene is referred to as an “oncogene”.    The diagram below illustrates how miRNA can inhibit a tumor suppressor mRNA and activate an oncogene.  Several naturally occuring foods have active ingredients that prevent tumor suppressor mRNAs from being silenced by miRNA, as well as preventing oncogene mRNAs from being translated into proteins. These natural foods include berries, green tea, soybeans, broccoli, and curry spice.

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How to “Reactivate” your Silenced Genes

The epigenetic silencing of “good genes” is not irreversible.  Natural compounds, when used on a regular daily basis can reverse this phenomena and reactivate silenced tumor suppressor genes.  The diagram below illustrates this:

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Specific Examples of Genes known to undergo epigenetic silencing

 It is important to point out that not all genes have CpG islands.  In humans, approximately half of the all genes have CpG islands, but the very important genes involving “housekeeping genes” and “tissue-specific genes” seem to have a disproportionate share of CpG islands.  These important genes are silenced by a combination of histone deacetylation and CpG island DNA methylation at the promoter sites.  This results in the inability of a transcription factor to access the gene and to bind to the promoter site.  With aging, many genes are silenced this way without any mutation of the DNA. There are some specific genes that are silenced via this epigenetic mechanism that play a huge role in aging. Here are some of them:

1. DNA repair gene inactivation by epigenetic silencing – Four examples of this are the genes hMLH1, MGMT, WRN, and BRCA1

hMLH1 – this an important gene for DNA mismatch repair, which is the way that microsatellite-unstable regions are repaired to avoid them becoming bigger.  Gene inactivation by CpG island hypermethylation has been observed at the promoter site for this gene

MGMT – this is an important gene for fixing mutant guanine bases that become chemically modified by a methyl or alkyl group.  This modification results in the “G” being read as a “A” (i.e. creating a G-to-A single nucleotide polymorphism).  MGMT removes the pro-mutagenic guanine residue.  Unfortunately, this gene is inactivated by CpG island hypermetylation with aging.

WRN – this is the gene responsible for Werner’s syndrome.  This gene codes for the WRN protein which has helicase and exonuclease activity.  With aging, the CpG island at the promoter site for this gene is hypermethylated, effectively silencing this gene.  As a consequence, the manifestations are a progeroid phenotype and increased risk of cancer due to extreme sensitivity to DNA damaging drugs or toxins.

BRCA1 – this gene is the most common gene that is mutated with hereditary breast cancer.  However in sporadic cases of breast and ovarian cancer, the BRCA1 gene can be silenced by CpG island hypermethylation in the promoter site of this gene.

2. Progeroid syndromes and atypical Werner’s syndrome – inactivation by epigenetic silencing. Two examples of accelerated aging genes – Lamin A/C and WRN

Laminin A/C – Mutations in the Laminin A/C gene produce a syndrome called Hutchinson’s Gilford progeria.  Although most progeroid syndromes are due to DNA mutations, we now know that a progeroid-like phenomena can be acquired due to epigenetic silencing of the same gene that is mutated in the hereditary form of HG progeria.  The Laminin A/C gene codes for two different laminin proteins that make up the scaffolding just inside the nuclear double membrane.  When this gene is hypermethylated at the promoter site, a syndrome called “atypical Werner’s syndrome” occurs.

WRN – this is called the “Werner gene” mentioned above.  It is mutated in classic Werner’s syndrome (WS).  Patients with WS develop accelerated aging and manifest cataracts, type II diabetes, osteoporosis, arteriosclerosis, and cancer at an earlier age and at increased incidence.  Cases of WS where the only problem is CpG island hypermethylation at the promoter site site.  Again, this is where we need a “DNA methylome” for proper diagnosis.

3. Alzheimer’s disease – Epigenetic “unsilencing” of PS1 and BACE genes. Alzheimer’s disease appears to be a multifactorial problem that is age-related. Epigenetic silencing is only one of the explanations for the disease.  Several explanations that involve epigenetic mechanisms may be involvedwith AD – homocystein/SAM dysregulation, DNA methylation/demethylation of genes, and the effects of folate and B12 deficiencies on the methylation status of genes involving AD.

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Naturally occurring phytochemicals that inhibit pathways that are known to be unregulated or dysregulated in cancer. 

Big Pharma is developing drugs to block most all of these pathways.  You can block them yourself by going for a walk in the jungle, the forests, or the mountains.

  You may notice a recurrent theme in the following table: the best health-producing natural plant substances may be found in the dumpsters of industrial plants that produce commodity food and drink substances like orange juice, wines, tomato ketchup, olive oil and applesauce. This is because the most-powerful naturally-produced stress resistant phytochemicals substances occur in the skins and rinds that are normally removed in the course of making commodity products. Skins are where oranges, grapes, tomatoes, olives, grapefruit, nuts, apples, and many other plants foods have found an evolutionary need to concentrate their chemical stress defenses. If we want to take advantage of the xenohormetic properties of these substances we have to find them where they are – today often in the dumpster.

Pathway Inhibited (or activated)  —    Compound Natural Sources of Compound

Nonspecific Tyrosine Kinase Inhibitors

genistein — soybeans – maybe we can get these from soy milk manufacturing plants

resveratrol — polygonum cuspidatum roots, Japanese knotweed, red grape skins

quercetin  — apple skins, onions, etc. – maybe we can get these from apple juice plant garbage

luteolin  — tomato skins – maybe we can get these from Campbell’s tomato soup plant

erbstatin — Streptomyces extract

itaconic acid — Aspergillus niger, Aspergillus terreus extract

staurosporine  — Streptomyces staurosporeus

beta-sitosterol  — saw palmetto, avocado, pumpkin seeds, cashew fruit, dandelion coffee, etc.

daucosterine a beta-sitosterol  — isolated from roots of Acanthopanax sessiliflorum

macrostemososide A  — ginseng

laxogenin  — Smilax sieboldi

chinenoside II  — Allium chinense (rakkyo)

ginsenoside  ed — Red Ginseng

icariside  — Epimedium grandiflorum, Epimedium sagittatum, E. thunbergianum, etc.

icaritin  — Epimedium brevicornu

EGFR tyrosine kinase inhibitors (above list) and:

lavendustin A  — streptomyces griseolavendus

herbimycin A  — streptomyces hygroscopium

other natural isoflavones

other natural quinolones

Angiogenesis inhibition

procyanidin oligomers

1,25-hydroxyvitamin D ?

emodin   — Oxygonum sinuatum

coleon A lactone — Plectranthus barbatus, Triphala churna (3 fruits) 

Vitamin E, EPA, DHA  — krill oil, fish oil, or myriad algae

mushrooms  —  “2nds” at mushroom farm                                   

curcumin  —    “left overs” from curry spice factory 

allyl mercaptan  — garlic

chloroplast glycoglycerolipids  —  spinach

proteoglycan molecules  — bindweed (Convolvulus arvensis) extract

Aromatase inhibitors

apigenin —

naringenin  — citris rinds from orange juice factory garbage

hesperitin  — citris rinds from grapefruit juice plant dumpster

mushroom polysaccharides  —  left-overs or surplus from mushroom farms

5alpha-reductase inhibitors

ECGC — tea plantation extra leaves, white tea surplus, Green tea surplus store

Mushroom extracts —  Ganoderma lucidum

Angiogenesis-related tyrosine kinase 

hydroxycinnamic acid — cinnamon farms, cinnamon factories

other forms of cinnamic acid

liposterolic extract of Serenoa repens

β-sitosterol

Beta-catenin inhibitors

Wild cherry bark extract — Prunus Serotina

Kras/Braf inhibitors

EPA, DHA — fish oil, krill oil, myriad algae

c-myc inhibitors

prenylated xanthones — mangosteen rinds from the mangosteen fruit packaging plant

garcinol  — mangosteen rinds from the mangosteen fruit dumpster behind the juice factory

Selective apoptosis inducers

boswellic acid — Frankincense that the Wise men forgot to take to Bethlehem

in cancer cells: pterostilbene  — Red Sandalwood oil on sale at 99 cents store (it’s not selling very well elsewhere), a-santol Red Sandalwood oil

ursolic acid  — apple skins from the apple pie factory and the apple juice factory dumpster

diosgenin — Wild Yam farm

charantin (b-stiosteryl) — Bitter Melon farm – no one is buying these melons for dinner

mormodin — Bitter Melon farm – we could get two for the price of one

allyl mercaptan  —  Garlic from Gilroy, CA – they make so much of it that the whole town stinks!

Vitex — Vitex Agnus-Castus farm

Icarisides  — Epimedium grandiflorum, Epimedium sagittatum, E. thunbergianum, etc.

Cellular senescence inhibitors

kinetin  — coconut water

trans-zeatin — coconut water

gibberellins —  I have no idea where to find these or if they are good for you

polyamines  —  I have no idea where to find these or if they are good for you

NF-kB inhibitors

curcumin  — curry powder factory left-overs

silymarin – milk thistle

Many other phytosubstances — In Vince’s Treatise, he lists 39 substances he takes as supplements that inhibit expression of NF-kappaB

COX2 inhibitors

EGCG, EGC  — green tea factory seconds. — white tea store sale

 FGF inhibitors — Gentisic acid rinds or skins of lots of fruits

HDAC inhibitors

ericifolin  — Allspice factory left overs

anacardic acid  — Cashew nut shell oil – you can buy this really cheap

cinnamic acid  — cinnamon farm

hydoxycinnamic acid  — cinnamon yard sales

procyanidins  — cinnamon factory

zerumbone  —  ginger factory – no one is buying this except in Japan

DNMT inhibitors

chlorogenic acid  — green coffee beans

caffeic acid  — green coffee beans

EGCG, EGC  — green tea

Genistein  — soybeans

Heat Shock Protein inhibitors

geldanamycin — Streptomyces hygroscopicus

PICK/Akt?mTOR inhibitors

caffeine (PI3K/Akt/mTOR) — green tea, coffee

xanthines —  cocoa (chocolate)

resveratrol (mTOR inhibition) — grape skins, wine

genistein (Pi3K/Akt) — soybeans

quercetin (mTOR) — apple peelings, onions, especially the outer layers

butein (PI3K/Akt) — Toxidodendron vernicifluum (aka Rhus vermocoflua)

capsaicin (PI3K/Akt) —  hot chili peppers

deguelin (Akt/mTOR) —roots of Lonchocarpus nicou

tocotrienol (Akt) — Vitamin E

ERK activators

soyasaponins  — soybeans

PPaR activators

lycopene, lutein, luteolin — Campbell’s tomato soup plant garbage dumpster

AMPK activators

resveratrol  — winery garbage, Welch’s grape juice plant waste, grape skins, Japanese knotweed

nduratin A  — Bitter melon extract

Galegene — guanidine derivative

Autophagy activators

apigenins

naringenin  — grapefruit rinds

resveratrol  — Japanese knotweed, grape skins

caffeine  — coffee, tea, etc.

capsaicin  —  hot chili peppers

FOXO3a activators

n-Tyrosol  — white winery

hydroxytyrosol  — white winery

secoiridoids  — olive oil pressing plant

Nrf2 activators

isothiocyanates —  broccoli, brussel sprouts, cabbage, cauliflower

lycopene, lutein  —  tomato skins

capsaicin  — hot chili peppers

pterostilbene — blueberries, grapes

EGCG  — green tea

(Nrf2 activators and NF-kappaB inhibitors tend to be the same)

Sirtuin activation

resveratrol  — grape skins

butein —  Rhus verniclfua

piceatannol food additive

fisetin  —  strawberries

quercetin  — capers, lovage, apples, tea, onions, citrus fruits, green vegetables

Klotho activation

Chinese herbs – selected Chinese herbs

Immune activators

beta 1,3 glucan  —  fungi cell walls

bacterial DNA — Lactobacillus fermentum extract

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See the important note on bioavailability of plant polyphenols and nano-particle delivery at the end of the  Part 3 blog entry.

DATA DISCLAIMER: 

The tables and compilations of data in this and the other blog entries in the Two Dragons series are intended to be illustrative of the main points to be made.  They are compiled from various sources, in most cases are incomplete, and may contain occasional errors.

MEDICAL DISCLAIMER:  FROM TIME TO TIME, THIS BLOG DISCUSSES DISEASE PROCESSES. THE INTENTION OF THOSE DISCUSSIONS IS TO CONVEY CURRENT RESEARCH FINDINGS AND OPINIONS, NOT TO GIVE MEDICAL ADVICE. THE INFORMATION IN POSTS IN THIS BLOG IS NOT A SUBSTITUTE FOR A LICENSED PHYSICIAN’S MEDICAL ADVICE. IF ANY ADVICE, OPINIONS, OR INSTRUCTIONS HEREIN CONFLICT WITH THAT OF A TREATING LICENSED PHYSICIAN, DEFER TO THE OPINION OF THE PHYSICIAN. THIS INFORMATION IS INTENDED FOR PEOPLE IN GOOD HEALTH. IT IS THE READER’S RESPONSIBILITY TO KNOW HIS OR HER MEDICAL HISTORY AND ENSURE THAT ACTIONS OR SUPPLEMENTS HE OR SHE TAKES DO NOT CREATE AN ADVERSE REACTION

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