Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer
Shuai Gao, Sujun Chen, Dong Han, Zifeng Wang, Muqing Li, Wanting Han, Anna Besschetnova, Mingyu Liu, Feng Zhou, David Barrett, My Phu Luong, Jude Owiredu, Yi Liang, Musaddeque Ahmed, Jessica Petricca, Susan Patalano, Jill A. Macoska, Eva Corey, Sen Chen, Steven P. Balk, Housheng Hansen He & Changmeng Cai
Nature Genetics (2020)Cite this article
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Abstract
FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1,2,3,4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.
There are a number of natural compounds that have been found to inhibit LSD1.
Just an observation...it can be hard for those of us who do not have a medical background to understand the import of studies like this. A few sentence summary of findings in layman terms would be extremely useful.
Sorry, this stuff is pretty dense. What I take from these studies is that it's worth using some safe well documented supplements because they are doing the same things many researchers are working on that may (if they can figure out how to patent them) become next generation drugs for PCa. Flavanoids like Quercitin, Baicalein(in Chinese Scullcap), Genistein(derived from soy), Apegenin, Fisetin, EGCG and many others all target the metabolic pathways that make a cancer cell different from a normal cell. These are available right now and make up a library of potential adjuvant cancer treatments.
I take Apegenin, Fisetin, Myracetin, Chinese Scullcap, Salvestrol, Curcumin(Theracuramin), Relora(Magnolia bark extract), Resveratrol, Ashwaganda, Astragalus, Reishi Mushroom extract. Some other supplements, repurposed drugs, but the ones listed are ones shown in studies to interfere with key pathways upregulated in PCa
Ever hear of Quassia? It comes from tropical areas and Surinam. My wife has HCL leukemia and is running out of options. She's had it since 1995. Quassia Amara also has effects on tumors so we're gonna start it tomorrow.
I have not heard of Quassia. A quick Google and find it mentioned in the same sentence as leukemia. If it's not overtly toxic and doesn't interfere with other medications deemed essential, why not? My sister in law passed away a few years ago from Leukemia. Hers was a myeloid variant and really a hard and difficult path she walked for those years. My heart is with you. She was treated at a major cancer center in NYC and wouldn't entertain any thought of a treatment beyond her doctors recommendations.
It looks like perhaps, danshen, curcumin and quercitin might be worth adding as they and/or their extracts came out on top of the list of natural inhibitors of HGMCL- a key enzyme implicated in HCL progression.
When researchers talk about LSD1, they are looking at an epigenetic change that alters cellular metabolism in specific ways associated with cancer development and progression. There may be hundreds, thousands or tens of thousands of such changes subtle and not so subtle that distinguish cancer cells from normal cells. For example, the extra cellular matrix(a kind of scaffolding between cells) changes as cancer metastasizes. Take a look at this metabolic map of PCa.
Detailed as this map seems, it represents a general and schematic picture of our understanding at one point in time of incredibly complex sets of processes. This map is divided into 9 sections. One can see that ERK1/2 and P53 activity is upregulated in more than one of these sections representing metabolic changes that cancer requires. So, some of these changes may be more important to interrupt than others. There are natural molecules that inhibit activity of both ERK1/2 (now often referred to as MAP)and P53 genetic pathways.
In the above study if one scrolls down to section 6. Classification of Flavonoids and Other Polyphenolic Compounds, one sees that Quercitin, Genistein, Baicalein and others overlapping with lists of natural LSD1 inhibitors.
These natural inhibitors are plant based molecules and compounds and often the studies are in vitro or sometimes animal models. As such, we don't have precise information on how many of the substances behave in the human body. What we do know is that many of them are safe to consume and we have co-evolved over tens of thousands of years with the plants that produce them.
One important variable you left out is amount: how much to take of each nutrient. While there is ample information on green tea and tumeric, there is hardly any useful material on some of the other nutrients. In my experience, whenever these numbers are available in amounts that have therapeutic significance , the amount translated into human diet is totally beyond what even supplements can provide (e.g., apegenin, fisetin, myracetin and salvestrol.)
Yes,and this is a difficulty in general with plant derived chemicals. Lots of epidemiological studies indicating that general consumption of fruits and vegetables is beneficial. Lots of studies of in vitro effects of specific chemicals like flavonoids on PCa and other cancers. It's the detailed in vivo in humans that's lacking. Even with the limited bioavailability and without the complete knowledge of the complex metabolic fate of these substances in the human body, they can still be worth taking at dosages available in supplements. This double blind observational study, ncbi.nlm.nih.gov/pmc/ , on colon cancer patients found significant positive outcomes for cancer recurrence with a control group consuming 20mg daily of apigenin and egcg.
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Genistein for PCa hormonal control.
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Nuclear Factor-kappaB [NF-kB]
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