Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

ABSTRACT: The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling¹ and is altered in over 20% of cancers^2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)⁺ forkhead box A1 (FOXA1)⁺ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic

SUBMITTER: Xiao L 

PROVIDER: S-EPMC8770127 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature