Function of the Androgen Receptor in Cancer Cells: Using genome editing to study AR Interactions with Cofactors.

Androgen Receptor (AR) is the principal mediator of the effects of androgen hormones in cells. Mutations in the AR gene lead to disorders of sex development (DSDs) resulting from androgen insensitivity, while aberrant activity of the AR drives the growth of prostate cancer cells. Much remains to be discovered about how mutations in the AR gene impact on its function in DSDs, and understanding AR molecular functions will ultimately accelerate the development of improved targeted therapies for prostate cancer.

Our previous work established that epigenetic regulator proteins are recruited to the ligand- binding domain (LBD) of AR via short motifs related to the sequence LXXLL (Heery et al., Nature 1997; Bevan et al., Mol Cell Biol 1999; Heery et al. JBC 2001; Chan et al., NAR 2014) and that AR coordinates expression of its cofactors via microRNAs (Nilsson et al., Oncotarget 2015) and is itself regulated by PIP5K1A (Miftakhova et al., Cancer Res 2016; Sarwar et al., Oncotarget 2016). We have employed yeast two hybrid assays to discovering novel cofactors (Chan et al., NAR 2014) or heterodimerisation profiles of Nuclear Receptors (Fulton et al., Cell Death & Disease 2017) including the AR. A PhD project is available to advance these novel findings using a range of techniques including protein-protein interactions, site-directed mutagenesis, assays of transcriptional activity, siRNA depletion, RNA-Seq and CRISPR CAS9 genome editing. We are using CRISPR to generate prostate cancer cell lines targeting AR and cofactors, providing essential tools for exploring the function of AR complexes. This offers an ideal system to study the impact of mutations in the LBD associated with cancer or androgen insensitivity syndromes. Our collaborators (Sweden, Belgium and the UK) have complementary expertise in structure determination and animal models of cancer.

Environment
The project will be carried out within the Gene Regulation & RNA Biology Group (circa 30 researchers) within the Division of Molecular & Cellular Sciences. The School of Pharmacy provides a vibrant cross-disciplinary research environment, with excellent support and training facilities for PG students.