Abstract
Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.
Highlights
The androgen receptor (AR) plays a central role in the development of prostate cancer (PCa)
To determine the function of Bag-1L, we employed a transcription activator-like effector nuclease (TALEN) approach that targets the first codon (CTG) of Bag-1L (Figure 1A), resulting in the complete knock-out (KO) of this protein
We used this approach in hormone-dependent LNCaP cells where we observed, concomitant with the loss of Bag-1L, an upregulation of the other Bag-1 isoforms (i.e. Bag-1S and Bag-1; Figure 1B); this is consistent with the translation of the Bag-1 mRNA by a leaky scanning mechanism
Summary
The androgen receptor (AR) plays a central role in the development of prostate cancer (PCa). Current approaches aimed at reducing persistent AR signaling either inhibit the production of androgens, or compete with endogenous ligands for binding to the AR C-terminal ligand-binding domain (LBD) (Helsen et al, 2014). While these therapies are initially effective in the advanced disease setting, PCa will eventually progress to a lethal, therapy-resistant state termed castration-resistant PCa (CRPC). IDRs can fold upon binding to their targets, allowing them to undergo conformational changes and participate in protein complex formations (Dyson and Wright, 2005) These interactions tend to be more transient and of lower affinity than complex formation between structured protein regions (Latysheva et al, 2015), they have become exceedingly important for controlling the function of IDR-containing proteins. Proteins that bind the unstructured AR AF-1 domain may constitute regulatory targets for inhibiting AR action
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