Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Lipid metabolism-focused CRISPR screen identifies NUS1 as essential for prostate cancer growth (#161)

Gio Fidelito 1 , Izabela Todorovski 2 3 , Leonie Cluse 2 3 4 , Renea Taylor 2 3 5 , Matthew Watt 1
  1. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
  2. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  4. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  5. Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Melbourne Urological Research Alliance (MURAL), Monash University, Melbourne, Victoria, Australia

Preclinical studies have demonstrated the effectiveness of targeting fatty acid uptake and oxidation in prostate cancer. However, targeting these processes may not be achievable in patients due to the essential requirement of fatty acids in different tissues, hindering the clinical translation of these therapeutics. We hypothesised that identifying essential proteins of lipid metabolism, downstream of fatty acid uptake, that are required for prostate cancer survival would provide the basis to develop novel strategies for treating prostate cancer.

We developed a bespoke human lipid metabolism knockout library, performed a CRISPR-Cas9 functional genomics screen, and identified genes that are essential for prostate cancer survival. These included genes that encode regulatory proteins within the mevalonate pathway (HMGCS1, PMVK, MVD) and those required for dolichol-N-glycosylation (NUS1, DHDDS, DOLK, DPAGT1), but not genes involved in cholesterol biosynthesis (FDFT1, SQLE, NSDHL, DHCR24, DHCR7). Independent studies showed that while depletion of enzymes within the mevalonate and dolichol-N-glycosylation biosynthesis pathway resulted in prostate cancer growth inhibition in vitro, only ablation of NUS1 led to a significant reduction in tumour growth in a subcutaneous xenograft model in vivo.

Mechanistically, loss of NUS1 resulted in the induction of stress-activated p38 MAPK signalling and ER stress response. Further analysis of AR and AR targets (KLK3 and NKX3-1) demonstrated downregulation of AR signalling upon NUS1 loss in xenografts. The combined effects of ER stress activation and dampening of AR signalling collectively resulted in the attenuation of prostate cancer growth. Loss of NUS1 enhanced AR antagonist (enzalutamide) sensitivity in prostate cancer spheroid culture.

These findings highlight the efficacy of a functional genomics approach to circumvent the current clinical challenges in targeting fatty acid uptake or oxidation for prostate cancer therapy. This study provides novel strategies for therapeutically targeting lipid metabolism for patients with prostate cancer.