Poster Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

Alternative splicing mediates androgen deprivation therapy resistance and metastasis in prostate cancer (#55)

Yesha Ramani 1 , Helen M Palethorpe 1 , Jacqueline Chang 1 , Daniel P Neumann 1 , Caroline A Chambers 1 , Julie Bracken 1 , John Toubia 1 , B Kate Dredge 1 , Andrew G Bert 1 , Thomas Tang 2 , Ladan Fazli 3 , Martin E Gleave 3 , Cameron P Bracken 1 , Katherine A Pillman 1 , Gregory J Goodall 1 , Luke A Selth 4 , Brett G Hollier 2 , Philip A Gregory 1
  1. Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
  2. Australian Prostate Cancer Research Centre, Queensland University of Technology, Brisbane, QLD, Australia
  3. Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
  4. Flinders Health and Medical Research Institute,, Flinders University, Bedford Park, SA, Australia

Alternative splicing is an important gene regulatory process that diversifies the transcriptome and proteome. We have previously identified an RNA binding protein called Quaking (QKI) that regulates alternative splicing during epithelial-mesenchymal transition. Here, we demonstrate that QKI is a key mediator of multiple stages of prostate cancer progression, including the development of resistance to androgen deprivation therapies (ADT) and metastasis. In clinical prostate cancer samples, QKI levels are markedly elevated in response to ADT and are further increased in castration resistant prostate cancer. In cultured cells, QKI is highly induced by the ADT Enzalutamide (ENZ) and modulates ENZ-induced alterations in cell plasticity, ENZ-resistance and metastasis in vivo. Transcriptomic and CLIP-seq profiling show that QKI modulates these effects by orchestrating a program of alternative splicing without major effects on mRNA levels. These studies demonstrate the existence of an alternative splicing program that impacts prostate cancer progression and therapy resistance.