Epitranscriptomic mechanisms of androgen signalling and prostate cancer

Abstract

Prostate cancer (PCa) is the second most common cancer diagnosed in men. While radical prostatectomy and radiotherapy are often successful in treating localised disease, post-treatment recurrence is common. As the androgen receptor (AR) and androgen hormones play an essential role in prostate carcinogenesis and progression, androgen deprivation therapy (ADT) is often used to deprive PCa cells of the pro-proliferative effect of androgens. ADTs act by either blocking androgen biosynthesis (e.g. abiraterone) or blocking AR function (e.g. bicalutamide, enzalutamide, apalutamide, darolutamide). ADT is often effective in initially suppressing PCa growth and progression, yet emergence of castrate-resistant PCa and progression to neuroendocrine-like PCa following ADT are major clinical challenges. For this reason, there is an urgent need to identify novel approaches to modulate androgen signalling to impede PCa progression whilst also preventing or delaying therapy resistance. The mechanistic convergence of androgen and epitranscriptomic signalling offers a potential novel approach to treat PCa. The epitranscriptome involves covalent modifications of mRNA, notably, in the context of this review, the N(6)-methyladenosine (m⁶A) modification. m⁶A is involved in the regulation of mRNA splicing, stability, and translation, and has recently been shown to play a role in PCa and androgen signalling. The m⁶A modification is dynamically regulated by the METTL3-containing methyltransferase complex, and the FTO and ALKBH5 RNA demethylases. Given the need for novel approaches to treat PCa, there is significant interest in new therapies that target m⁶A that modulate AR expression and androgen signalling. This review critically summarises the potential benefit of such epitranscriptomic therapies for PCa patients.

Fig. 1

Structure of the androgen receptor and its splice variants. Schematic representation illustrating the comprehensive structure of the androgen receptor (AR), including annotated domains, amino acid lengths and splice variants.

Fig. 2

Therapeutic targets in androgen deprivation therapy (ADT) in prostate cancer. Demonstration of therapeutic targets targeted by ADT for treating prostate cancer, outlining the clinical molecular targets together with their respective analogues and antagonists.

Fig. 3

The components of the m⁶A methyltransferase complex, including m⁶A methylases, demethylases and “reader” proteins involved in dynamic mRNA modification. Representation of the components of the m⁶A methyltransferase complex comprising the methylases (“writer” proteins) and the demethylases (“eraser” proteins), together with the effector "reader” proteins that bind to m⁶A modifications both within the nucleus and cytoplasm of cells.

Fig. 4

The m⁶A methyltransferase complex and its associated roles. Illustration of the dynamic interactions, catalytic activities, and functions of the m⁶A methyltransferase complex in mRNA selection, androgen signalling and AR expression, immune response, DNA repair response and translational regulation.