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.
Cell Line, Tumor, Humans, Receptor, erbB-2, Receptors, Androgen, Neoplasm Staging, Signal Transduction, Male, Kruppel-Like Transcription Factors, Transcriptional Activation, Neuroendocrine Cells, Prostatic Neoplasms, Castration-Resistant
U.S. Department of Health & (R01CA174777)
NCI NIH HHS (R01 CA212097, R37 CA241486, R01 CA174777, R01 CA204856, R01 CA229618, R37 CA230617)
External DOI: https://doi.org/10.1038/s41467-021-26612-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332207
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/