Epitranscriptomic Determinants of Aggressive Prostate CancerTools Haigh, Daisy (2021) Epitranscriptomic Determinants of Aggressive Prostate Cancer. PhD thesis, University of Nottingham.
AbstractProstate cancer (PCa) is a leading cause of cancer-related deaths. The androgen receptor (AR), a ligand-dependent transcription factor that influences gene expression and alternative splicing, plays a pivotal role in PCa pathogenesis and is a key driver of tumour progression and therapy resistance. Given this critical role, androgen deprivation therapies (ADTs) that target the AR or inhibit androgen production are the mainstay of systemic PCa treatment. Whilst ADTs effectively inhibit PCa growth and progression, the treatment window where ADTs remain efficacious is limited due to the development of castration-resistant prostate cancer (CRPC) which arises through multiple mechanisms including alternative splicing of the AR, generating constitutively active AR splice variants which evade currently approved ADTs and are thus a critical and unmet clinical need. The N6-methyladenosine (m6A) RNA modification is involved in gene regulation, alternative splicing and translation, and is implicated in numerous solid and haematological cancers, thus this thesis aimed to explore the function of m6A in global gene regulation and alternative splicing in the context of PCa with a focus on the role of m6A in androgen signalling and AR-mediated alternative splicing, including alternative splicing of the AR. To this end, this study investigated the expression and function of the m6A ‘writer’ and ‘eraser’ proteins METTL3 and FTO, which catalyse the methylation and demethylation of the m6A modification, in PCa cell lines and patients. Functional modulation of the m6A regulators was performed to investigate the role of m6A in PCa; inducible shRNA-mediated METTL3 knockdown and CRISPR-Cas9 knockout of FTO identified an important role for m6A in the global regulation of gene expression and alternative splicing, including the AR itself. Analysis of the global m6A modifications in enzalutamide-sensitive (LNCaP:C4-2) and the enzalutamide-resistant (22Rv1) CRPC cell lines identified differences in their global epitranscriptomic landscapes and importantly, a disparity in the m6A modifications of the AR. This study thus implicates m6A in the regulation of AR expression and alternative splicing, identifying a potential novel therapeutic target for the prevention, delay and reversal of ADT resistance and CRPC development through the generation of AR alternative splice variants.
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