Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.
Munro, Sarah A
Severson, Tesa M
Selth, Luke A
Springer Science and Business Media LLC
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Che, M., Chaturvedi, A., Munro, S. A., Pitzen, S. P., Ling, A., Zhang, W., Mentzer, J., et al. (2021). Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.. Nat Commun, 12 (1) https://doi.org/10.1038/s41467-021-26612-1
Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.
Article, /631/45/612/822, /631/67/589/466, /13/106, /45/15, /45/91, /38/39, /38/89, /13/1, /13/105, /13/109, /42/44, article
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (R01CA174777)
External DOI: https://doi.org/10.1038/s41467-021-26612-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330288