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

GSE266853 Homo sapiens Expression profiling by high throughput sequencing 9 samples Submitted 2025/01/27 Platform GPL24676
Summary
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.
Published in
Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer
Pitzen SP, Rudenick AN, Qiu Y et al. · Proceedings of the National Academy of Sciences of the United States of America 2025 · PMID 39913208 · doi:10.1073/pnas.2415308122
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Also filed as BioProject PRJNA1108521 and SRA study SRP506072. Searching any of these in the dataset finder brings you back here.

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