Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity

Abstract

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails extensive epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer, although they can lead to muscular atrophy. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC and muscular atrophy.

A Liquid–Liquid Phase Separation-Related Index Associate with Biochemical Recurrence and Tumor Immune Environment of Prostate Cancer Patients

“…The liquid–liquid phase separation (LLPS) especially acts on the dysregulation of epigenetics, which could lead to the tumorigenesis and tumor progression [ 21 , 22 , 23 ]. A number of recent studies consider LLPS as a novel therapeutic target of cancer intervention [ 21 ], similarly in prostate cancer [ 19 ]. However, there were limited studies that focused on exploring the correlation between LLPS and PCa, especially the BCR of PCa.…”

“…Therefore, targeting LLPS-mediated transcription factor (TF) and the formation of LLPS on enhancers to reprogram treatment-resistant tumor cells for preventing the progression of PCa seemed feasible [ 16 , 18 ]. Another study hypothesized that polyQ-dependent LLPS could potentially provide new therapies against castration-resistant prostate cancer (CRPC) by leading to the inhibition of transcriptional activity of AR [ 19 ]. However, to our knowledge, the studies which focus on exploring the correlation between LLPS and PCa, especially the BCR of PCa, are still limited.…”

The evolution and polymorphism of mono-amino acid repeats in androgen receptor and their regulatory role in health and disease

“…Recently, it was reported that AR forms condensates in the nucleus, and elevated nuclear localization was observed despite decreased transcriptional activity with increasing length of polyQ1 ( 202 ). This work is very preliminary, and further studies will be needed to elaborate whether increase in polyQ1 length results in phase separation and/or aggregation.…”

“…However, the AR-DBD was identified as a minimal region capable of driving LLPS in the presence of polyU ( 201 ). Another recent study showed that the length of the polyQ affects nuclear localization and hence the transcriptional activity of AR ( 202 ). This suggests that despite AR-NTD being insufficient for driving LLPS alone, it still has a regulatory role, probably by determining solubility via the length of the polyQ1 and recruiting co-factors that can alter the LLPS propensity.…”

“…However, this research direction is still poorly understood, although there is increasing attention in the cell biology field to explore this new modality for regulation of certain molecular functions. For example, AR can constitute part of enhanceosomes ( 200 , 202 – 204 ), hence overactivation of transcription in cancer should also be studied in the contexts of liquid-like phase separated condensate-state. The importance of LLPS raises the mechanistic question of the role of different domains (driver, regulatory or passive region), and polymorphic and splice variants, of AR in biomolecular condensate formation (transcriptional condensates, enhanceosomes) in late stages of PCa.…”