LSD1 Has Dual Functions As A Major Regulator Of Androgen Receptor Transcriptional Activity

[Terma]

I don't have much to say on this, I'm posting it to complete the picture about this thing. There are more articles than this about LSD1 and the AR.

Lysine Specific Demethylase 1 has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

Lysine Specific Demethylase 1 has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity
Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates.

It can both prevent and potentiate the AR's effects through demethylating different histones/subunits/non-histones.

You have to read the discussion for some clarification, but another article does it a little better:

Androgen Receptor Gene Expression in Prostate Cancer is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine Specific Demethylase 1

LSD1 was initially identified in corepressor complexes and shown to function by demethylating mono- and dimethylated H3K4 (Shi et al., 2004). However, it was subsequently shown to function as a coactivator through demethylation of repressive mono- and dimethylated H3K9 when associated with AR and possibly other nuclear receptors including estrogen receptor α (Metzger et al., 2005, Garcia-Bassets et al., 2007, Perillo et al., 2008). The results of this study indicate that the association with AR does not determine the coactivator versus corepressor function of LSD1, and that it is instead determined by properties of the element to which it is being recruited. For example, hypoacetylated nucleosomes are more susceptible substrates for LSD1 mediated demethylation (Shi et al., 2005). Moreover, recent data indicate that phosphorylation of H3T11 by an AR associated kinase (PRK1/PKN1) enhances the demethylation of H3K9me3 by JMJD2C and subsequent demethylation of H3K9me1,2 by LSD1 (Metzger et al., 2008), while phosphorylation of H3T6 by a distinct kinase (PKCβ1) can suppress the LSD1 mediated demethylation of H3K4me1,2 (Metzger et al., 2010). Our data indicate that lower H3T6 and H3T11 phosphorylation may contribute to the substrate specificity and corepressor function of LSD1 at AR repressed genes, although LSD1 may be regulated by a distinct mechanism on the TMPRSS2 gene. It will clearly be important to further characterize these and additional AR suppressor elements and determine the extent to which histone modifications or other factors regulate the function of AR and LSD1 on these suppressor versus AR enhancer elements.

In other words the behavior of LSD1 depends on other factors which I don't know but would be nice to know.

You can tell for better or worse this thing is pretty important and involved in all different types of pathology.

 

[Terma]

I posted this: Grant Genereux's Theory Of Vitamin A Toxicity

Almost forgot:
Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia

There's more than one way to see this, but surely LSD1 prevented the (circumstantially beneficial) effects of ATRA in unscrewing cancer. LSD1 is a FAD/folate-binding protein.

It'd be interesting to find out what exactly triggers the supposed LSD1 increase in ATRA cancer treatment, which leads to ATRA losing its effect. Perhaps it suggests ATRA indirectly leads to increased LSD1, perhaps as a feedback mechanism.

LSD1 is the same demethylase used by the androgen receptor for feedback: LSD1 Has Dual Functions As A Major Regulator Of Androgen Receptor Transcriptional Activity
and at high activity represses the signal (prostate cancer may be from lowish-but-constant androgen stimulation, or yet again some problem with histones).

It's also worth pointing out, if LSD1 is high and folate (and NAD) is deficient, it generates formaldehyde in the nucleus:
Histone demethylase LSD1 is a folate-binding protein
It's not very quantified, but you can see the problem.

Here's the proof of concept:

Retinoic acid receptors and LSD1 as novel targets for prostate cancer

Castration resistant prostate cancer (CRPC) is the most aggressive and lethal form of prostate cancer (PCa) and novel therapies are required for its treatment. Epigenetic and genetic alterations are very common in CRPC cells and contribute to the cancer phenotype by promoting aberrant gene expression. Nuclear receptors, modulated by co-repressor and co-activator complexes, orchestrate the cells transcriptional landscape to activate and repress downstream pathways, ultimately affecting cell growth and survival. Retinoic acid receptors (RAR) are retinoic acid (RA) regulated nuclear receptors that play a key role on cell differentiation and can induce apoptosis in tumor cells. On the other hand, LSD1, a co-regulatory protein, is overexpressed in cancer tissues and alters the activity of the androgen receptor, driving carcinogenesis. In RA resistant acute myeloid leukemia cells, inhibition of LSD1 reactivates RA induced differentiation and combinatorial therapy of a LSD1 antagonist and all-trans RA promotes apoptosis. We suggest a combinatorial therapeutic approach by inhibiting LSD1 and activating RAR. To determine whether gene expression patterns involving LSD1 and RAR are altered in the tumor tissue, RNA-Sequencing (RNA-Seq) data from 52 matched normal and tumor samples available from the cancer genome atlas (TCGA) database were analyzed using R programming language (limma package). Approximately 28% of the retinoid metabolism genes, 11% of RAR and 10% of LSD1 signature genes were differentially expressed with a log2 FC > ±1 and FDR < 0.05. All three subtypes of RARs and their heterodimeric partners retinoid X receptors (RXRs), also a great majority of the retinol metabolism genes were significantly downregulated in the tumor tissue. Additionally majority of the genes that are involved in RA metabolism and signaling showed a significant negative correlation to LSD1 expression. Subsequently, cell proliferation assays were performed on stably transfected shLSD1 LNCaP-C4-2 (C4-2) cells, treated with RA or vehicle control, to evaluate the phenotypical consequences of targeting RAR and LSD1. C4-2 cells treated with RA in combination with LSD1 knock-down showed significantly higher inhibition of proliferation when compared to control or RA treated control cells. Additionally, in order to analyze the effect of the combinatorial therapy with LSD1 inhibition and ATRA treatment on the C4-2 cell transcriptome, RNA-Sequencing experiment was conducted on LSD1-targeted shRNA transfected C4-2 cells. LSD1 inhibition enhanced the transcriptional response to ATRA and modulated apoptotic pathways. These results suggest the relevance of a combinatorial therapeutic approach targeting LSD1 and RAR in CRPCa cells.

 

[Terma]

And here we go... this is 10 years old btw, can't believe I missed this:

p53 is regulated by the lysine demethylase LSD1. - PubMed - NCBI

p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.

LSD1 directly prevents ATRA from inducing p53 gene. There could be more somewhere, but this is quite significant on its own.

 

[Terma]

This is basically the gene that controls everything, even goes beyond histones and demethylates Dnmt1:

The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. - PubMed - NCBI

Histone methylation and DNA methylation cooperatively regulate chromatin structure and gene activity. How these two systems coordinate with each other remains unclear. Here we study the biological function of lysine-specific demethylase 1 (LSD1, also known as KDM1 and AOF2), which has been shown to demethylate histone H3 on lysine 4 (H3K4) and lysine 9 (H3K9). We show that LSD1 is required for gastrulation during mouse embryogenesis. Notably, targeted deletion of the gene encoding LSD1 (namely, Aof2) in embryonic stem (ES) cells induces progressive loss of DNA methylation. This loss correlates with a decrease in DNA methyltransferase 1 (Dnmt1) protein, as a result of reduced Dnmt1 stability. Dnmt1 protein is methylated in vivo, and its methylation is enhanced in the absence of LSD1. Furthermore, Dnmt1 can be methylated by Set7/9 (also known as KMT7) and demethylated by LSD1 in vitro. Our findings suggest that LSD1 demethylates and stabilizes Dnmt1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems.

 

[olive]

Very interesting, not sure if I understand the implications fully. Do you think cryptotanshinone (LSD1 inhibitor) could be used to prevent hair loss?