Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 28, Issue 20, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115712
Keywords
AR-V7; Indisulam; Alternative splicing; RBM39; Prostate cancer; Androgen receptor
Funding
- NIH [1F32CA236347-01, R01 CA227025, 1R01CA221969-01, 1R01CA244550]
- PCF YI and Challenge grants
- Benioff Initiative for Prostate Cancer Research
- Howard Hughes Medical Institute
- Samuel Waxman Cancer Research Foundation
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Alternative splicing of the androgen receptor (AR) is frequently observed in castration resistant prostate cancer (CRPC). One AR isoform, the AR-V7 splice variant, is a constitutively active transcription factor which lacks a ligand binding domain and is therefore undruggable. AR-V7 expression correlates with resistance to androgen receptor signaling inhibitors (ARSi) and poor clinical prognoses. The occurrence of the AR-V7 splice variant is driven by alternative splicing of AR pre-mRNA by the spliceosome, however the mechanistic details are poorly understood. We demonstrate that the splicing factor RBM39 is critical for alternative splicing of the AR-V7 splice variant mRNA transcripts from AR pre-mRNA, and that the anti-cancer drug, indisulam, reduces AR-V7 mRNA levels by degrading RBM39. We report that indisulam effectively reduces AR-V7 in in vitro and in vivo models.
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