KLF5 promotes a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer

Inhibiting the androgen receptor (AR) is effective for advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine identity (NEPC) or double negative CRPC lacking luminal and neuroendocrine identity (DNPC). Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of DNPC growth and expression of genes defining this mixed basal, club, and hillock cell identity. KLF5-mediated upregulation of RARG exposed a DNPC growth sensitivity to retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer new CRPC classifications based on prostate epithelial cell identities, and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity. To investigate the effects of knockdown of KLF5 on gene expression in LTL331CL, we knocked down KLF5 with 2 independent siRNAs or control siRNA. Cells were maintained in LTL331CL-specific media for 72 hours before collection. Three biological replicates were performed for each siRNA (siC, siKLF5-1, siKLF5-2 for n=9 total samples sequenced).