Up - regulation of androgen receptor by heat shock protein 27 and miR - 1 induces pathogenesis of androgenic alopecia

[jamesbooker1975]

Really interesting new study .

Up - regulation of androgen receptor by heat shock protein 27 and miR - 1 induces pathogenesis of androgenic alopecia

 

[jamesbooker1975]

So, basically, it is an up regulation of our androgen receptor in our follicles. So , it is not that we have more DHT, it mean that we have more androgens activate it to receive that DHT, of course higher DHT levels will cause more agressive hair loss . But are that two them " heat shock proteins" what cause the whole damn problem and it explain why most people don't start to bald when their are teenager cause when is when they have their higher Androgens levels .

 

[Armando Jose]

study 2008

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function - PubMed

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent...

pubmed.ncbi.nlm.nih.gov

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function.

Abstract

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90.

 

[Kagaho]

AR sensitivity rather than DHT levels its been known for ages.

 

[jamesbooker1975]

AR sensitivity rather than DHT levels its been known for ages.

This is total differnt, it is not sensitivity. Did you even bother to read it ? Are not more sensitive, are more , that are two different things. And are more, cause that two damn proteins are being active .
So, basically, what you are telling is that , since "ages " science have being wrong about this .

 

[-specter-]

I hope it can somehow help get my hair back as soon as possible

 

[Dimitri001]

I'm kinda surprised by the lack of response to this study/thread. I mean, I'm not very knowledgeable on the more granular level of Androgenetic Alopecia mechanics, but isn't this kinda significant info? I mean, it appears it's not NEW info, given the 2008 study Armando posted, but I've never heard this mentioned in any explanations of Androgenetic Alopecia, so it seems SORT OF like new info.

Is there a way to target this protein for therapeutic ends? Has anyone ever tried? Can we reasonably speculate on the magnitude of effect if we were able to get at this protein and restore normal functioning?

 

[jamesbooker1975]

I'm kinda surprised by the lack of response to this study/thread. I mean, I'm not very knowledgeable on the more granular level of Androgenetic Alopecia mechanics, but isn't this kinda significant info? I mean, it appears it's not NEW info, given the 2008 study Armando posted, but I've never heard this mentioned in any explanations of Androgenetic Alopecia, so it seems SORT OF like new info.

Is there a way to target this protein for therapeutic ends? Has anyone ever tried? Can we reasonably speculate on the magnitude of effect if we were able to get at this protein and restore normal functioning?

Yes, It is such a good thing cause
1) It explain the real cause
2) It show future tarjet approach .

Well, I think that most people ( specially most in their 20s ) just want a youtuber selling you a product , that is the real problem. They Want Derek from more plates more dates selling you something in base of an study . If not, is not important .

 

[waynakyo]

LOL I now know that no one reads the published studies section. Yes it is a very interesting study, need more discussion.

AR sensitivity rather than DHT levels its been known for ages.

That was my understanding until I saw several papers showing actual DHT levels higher in balding areas, in a controlled study. I will try to find them and share. Was pretty surprised tbh

 

[Feramon1]

Interesting topic. Are there any thoughts on how to test this in practice?

 

[pegasus2]

Interesting topic. Are there any thoughts on how to test this in practice?

From the post I linked to:

One proposed mechanism is that HDAC inhibitors target HDAC6 which deacetylates HSP90 and decreases AR stability [55]. Furthermore, HDAC inhibitors directly suppress AR transcription [54,56].

we identified the master chaperone, heat shock protein 90α (HSP90α), as a prolactin-Janus-Kinase-(JAK2)-signal-transducer-and-activator-of-transcription-5-(STAT5) target gene involved in survival, and here we investigated the role of HSP90 in the mechanism of prolactin-induced viability in response to DNA damage

 

[jamesbooker1975]

LOL I now know that no one reads the published studies section. Yes it is a very interesting study, need more discussion.

That was my understanding until I saw several papers showing actual DHT levels higher in balding areas, in a controlled study. I will try to find them and share. Was pretty surprised tbh

I read a paper where it was elevete in youngers people that bald ( teen , specially , compare to place ) but not high in older people ( and by older I mean olders than 20s ) .
May be , it is both things and people that bald really young, in their teens have both things( higher dht levels plus more receptors )

 

[pegasus2]

This study may be relevant here. It's accepted within this field of research that people who do not go bald, in general, go grey early. Prolactin's hsp90-mediated promotion of ATM might have something to do with that. While Prolactin is promoting miniaturization by inducing hsp90 and through other pathways, it may be protecting hair pigment at the same time. A lot of people have a significant amount of grey hair on the sides where they aren't prone to baldness, but little on top. ATM promotes HSP27. ATM promotes ROS protection and DNA repair, and its inhibition causes hair loss, so ATM itself probably doesn't cause miniaturization.

Stress-sensing in the human greying hair follicle: Ataxia Telangiectasia Mutated (ATM) depletion in hair bulb melanocytes in canities-prone scalp - Scientific Reports

Canities (or hair greying) is an age-linked loss of the natural pigment called melanin from hair. While the specific cause(s) underlying the loss of melanogenically-active melanocytes from the anagen hair bulbs of affected human scalp remains unclear, oxidative stress sensing appears to be a key...

www.nature.com

ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair - PubMed

Ataxia telangiectasia (A-T) is a human disease caused by ATM deficiency characterized among other symptoms by radiosensitivity, cancer, sterility, immunodeficiency and neurological defects. ATM controls several aspects of cell cycle and promotes repair of double strand breaks (DSBs). This...

pubmed.ncbi.nlm.nih.gov

 

[Bread24]

This study may be relevant here. It's accepted within this field of research that people who do not go bald, in general, go grey early. Prolactin's hsp90-mediated promotion of ATM might have something to do with that. While Prolactin is promoting miniaturization by inducing hsp90 and through other pathways, it may be protecting hair pigment at the same time. A lot of people have a significant amount of grey hair on the sides where they aren't prone to baldness, but little on top. ATM promotes HSP27. ATM promotes ROS protection and DNA repair, and its inhibition causes hair loss, so ATM itself probably doesn't cause miniaturization.

Stress-sensing in the human greying hair follicle: Ataxia Telangiectasia Mutated (ATM) depletion in hair bulb melanocytes in canities-prone scalp - Scientific Reports

Canities (or hair greying) is an age-linked loss of the natural pigment called melanin from hair. While the specific cause(s) underlying the loss of melanogenically-active melanocytes from the anagen hair bulbs of affected human scalp remains unclear, oxidative stress sensing appears to be a key...

www.nature.com

ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair - PubMed

Ataxia telangiectasia (A-T) is a human disease caused by ATM deficiency characterized among other symptoms by radiosensitivity, cancer, sterility, immunodeficiency and neurological defects. ATM controls several aspects of cell cycle and promotes repair of double strand breaks (DSBs). This...

pubmed.ncbi.nlm.nih.gov

So the induction of hsp90 by prolactin should be the reason why hmi115 did get such good results in these animal trails? Really good find

 

[inmyhead]

study 2008

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function - PubMed

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent...

pubmed.ncbi.nlm.nih.gov

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function.

Abstract

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90.

topical genistein worth to try?

Nvm, seems like some members tried it and got no results.

 

[Kagaho]

This is total differnt, it is not sensitivity. Did you even bother to read it ? Are not more sensitive, are more , that are two different things. And are more, cause that two damn proteins are being active .
So, basically, what you are telling is that , since "ages " science have being wrong about this .

I haven't read it yet but it seems interesting beforehand.

The more AR receptors within the HF, the greater the sensitivity to DHT.

Come on, it's not that hard.

 

[Armando Jose]

topical genistein worth to try?

Nvm, seems like some members tried it and got no results.

No results? How long?
Probably topcal genistein is a free sides

 

[pegasus2]

Ivermectin works in prostate cancer through this mechanism.

Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models - PubMed

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep...

pubmed.ncbi.nlm.nih.gov

 

[pegasus2]

I think the study in the OP hit on something really big.

Below is a study on prostate cancer pathogenesis. BPH, PC and Androgenetic Alopecia are very much the same in etiology I believe. They are strongly associated, and the treatements that work on BPH/PC work on Androgenetic Alopecia.

silencing Hsp27 decreased IL-6-dependent STAT3 phosphorylation, nuclear translocation, and STAT3 binding to the Twist promoter, suggesting that Hsp27 is required for IL-6-mediated EMT via modulation of STAT3/Twist signaling. We observed a correlation between Hsp27 and Twist in patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer.

Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer - PubMed

Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-to-mesenchymal transition (EMT), and the mechanisms that control the process of EMT...

pubmed.ncbi.nlm.nih.gov

Twist inhibition promotes a prolonged anagen phase in mice. As it turns out HSPs upregulate Twist.

Another cancer study:

Our findings reveal that HSP90 promotes the binding of STAT3 to the TWIST1 promoter, leading to the transcription of TWIST1. The inhibition of HSP90 downregulates STAT3 activity and TWIST1 transcription, thereby suppressing EMT and potentially inhibiting tumor progression, metastasis, and chemoresistance in different types of cancers.

Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription - PubMed

Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT...

pubmed.ncbi.nlm.nih.gov

This is a very old paper from Ralf Paus in which they found that HSP expression increased during the final phase of anagen and into catagen, decreasing after telogen.

Immunoreactivity for HSPs 27, 60, and 72 in the hair bulb increased significantly during anagen VI and the catagen transformation of the follicle, and decreased again abruptly with completion of the catagen-telogen transformation. The expression pattern of HSPs 60 and 72 in situ was cytoplasmic, whereas that of HSP 27 was both cytoplasmic and nuclear. Conclusions: These observations suggest that the synthesis of HSPs by hair bulb keratinocytes is related to the anagen-catagen transformation of the follicle

Here is the paper on Twist1 knockout:

On P23, the Twist1f/f hair follicles had just started the anagen phase of the second hair cycle. This anagen phase was sustained to approximately P40, and then was followed by the catagen phase observed at P45 and the telogen phase observed at P54 and P61 (Figure 5A). In contrast, the Twist1Δ/Δ hair follicles always remained in the anagen phase, as histologically examined on P21, P23, P29, P34, P37, P40, P45, P54, and P61 (Figure 5A). A schematic comparison of these differences in the hair follicle growth cycle is presented in Figure 5B. These results clearly indicate that Twist1 plays an essential role in maintaining the hair growth cycle by converting the anagen phase into the catagen phase, which is then followed by the telogen phase. The loss of Twist1 function keeps the hair growth cycle at its anagen phase in adult mice.

These results further support the notion that inducible knockout of Twist1 in young mice leads to arrest of the hair follicle cycle at the anagen phase in adulthood.

It would seem that AR activation upregulates the PRLR, which induces HSPs, and those HSPs increase AR transcription, creating a positive feedback loop keeping Twist1 expression high and causing premature catagen through HSP-mediated Twist upregulation.

I made a thread before about Twist1 and the potential to inhibit it. There weren't any good ways to do this, and there still aren't. However, this provides us with more options. If we can inhibit HSP90 and HSP27 then perhaps we can cure this thing. HSP27 is upregulated by HSP90 so maybe just targeting HSP90 would be enough? There are a lot of HSP inhibitors in development. Unfortunately most of them have serious safety concerns. https://sci-hub.se/https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.9b00940

An indirect option for targeting HSP90 is HDAC inhibitiors.

 

[jamesbooker1975]

I think the study in the OP hit on something really big.

Below is a study on prostate cancer pathogenesis. BPH, PC and Androgenetic Alopecia are very much the same in etiology I believe. They are strongly associated, and the treatements that work on BPH/PC work on Androgenetic Alopecia.

Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer - PubMed

Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-to-mesenchymal transition (EMT), and the mechanisms that control the process of EMT...

pubmed.ncbi.nlm.nih.gov

Twist inhibition promotes a prolonged anagen phase in mice. As it turns out HSPs upregulate Twist.

Another cancer study:

Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription - PubMed

Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT...

pubmed.ncbi.nlm.nih.gov

This is a very old paper from Ralf Paus in which they found that HSP expression increased during the final phase of anagen and into catagen, decreasing after telogen.


Here is the paper on Twist1 knockout:



It would seem that AR activation upregulates the PRLR, which induces HSPs, and those HSPs increase AR transcription, creating a positive feedback loop keeping Twist1 expression high and causing premature catagen through HSP-mediated Twist upregulation.

I made a thread before about Twist1 and the potential to inhibit it. There weren't any good ways to do this, and there still aren't. However, this provides us with more options. If we can inhibit HSP90 and HSP27 then perhaps we can cure this thing. HSP27 is upregulated by HSP90 so maybe just targeting HSP90 would be enough? There are a lot of HSP inhibitors in development. Unfortunately most of them have serious safety concerns. https://sci-hub.se/https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.9b00940

An indirect option for targeting HSP90 is HDAC inhibitiors.

May be on one of that Heat Shock Protein 90 Inhibitors will not go systemic if go topical. Orally is out of the question. The " cure " will be topically, for sure.