Exploring the landscape of androgen receptor binding at tRNA genes in prostate cancer

Prostate cancer (PCa) presents a major global health burden, with 1.47 million new diagnoses and approximately 397,000 deaths each year. Dysregulated androgen receptor (AR) signalling is a primary driver of PCa progression, and consequently a key therapeutic target through androgen deprivation therapies and AR antagonists. Abnormal tRNA expression has been observed in different cancer types, including breast and ovarian, and there is evidence of estrogen and progesterone receptors binding tRNA genes. However, potential AR targeting of tRNA genes remains unexplored in the literature. Previous unpublished work (White group, University of York) found preliminary evidence of AR and H3K27ac enrichment (measured by ChIP-sequencing) at a subset of tRNA genes in the androgen-responsive and AR-expressing LNCaP cell line. The FOXA1 pioneer factor (a transcription factor capable of binding and opening heterochromatin), frequently co-localised with AR-binding, suggesting a possible interaction. However, depletion of the SWI/SNF chromatin remodeler significantly increased AR and H3K27ac signal intensity, indicating a potential tumour suppressive role. The current study built on these findings by first validating AR and FOXA1 binding at tRNA genes in tumour biopsies taken from patients with PCa, highlighting the biological relevance in disease. Next, the effect of different co-factors and chromatin remodelers were examined. FOXA1 overexpression enhanced existing AR recruitment to tRNA genes in addition to promoting de-novo binding events, consistent with its role as a pioneer factor. Analysis of local chromatin accessibility revealed that tRNA genes enriched for AR, FOXA1 and H3K27ac were highly accessible. Loss of the SWI/SNF and CHD1 chromatin remodelers resulted in increased accessibility and AR binding, respectively, suggesting tumour suppressive roles in AR recruitment to tRNA genes. Moreover, c-Myc frequently co-localised with AR at tRNA genes. Together, these findings strengthen evidence for AR binding at a subset of tRNA genes in PCa and highlight the relevance to human disease.