Identification of critical hypoxia-induced factors in prostate cancer treatment resistance

Functional validation demonstrated that silencing KMT2C and KMT2D reduced survival by 40% under hypoxia but not normoxia. RNA-seq analysis revealed hypoxia-driven reprogramming of ribosomal, metabolic and stress-response pathways, consistent with activation of the integrated stress response (ISR). The IR screen identified DNA damage repair genes (e.g., PRKDC, XRCC4, NHEJ1) as major dependencies, while positively selected genes suggested adaptation.

To complement this approaches, BioID-based proximity labelling coupled with mass spectrometry was performed in PC-3 cells expressing full length androgen receptor (AR-WT). This identified canonical AR cofactors (e.g., FOXA1, HOXB13, SWI/SNF complex) and stress-induced interactions, including RA1, PHF14, HMG20A and USP34. Collectively, this work provides a multi-omics framework integrating CRISPR and functional genomics, transcriptomics, and proteomics to identify chromatin and translational regulators as potential therapeutic targets and biomarkers of CRPC progression.<br><br><i>Thesis is embargoed until 31 July 2031.</i><br>