期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26612-1
关键词
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资金
- NIH [R01CA174777, R01CA212097, R37CA230617, R01CA204856, R01CA229618, R37CA241486]
- Prostate Cancer Foundation Challenge Awards
- DOD PCRP [W81XWH-19-1-0161, W81XWH-17-1-0653]
- National Health and Medical Research Council of Australia [1121057]
- Avon Foundation for Women
- University of Minnesota Faculty Research Development Grant
- Principal Cancer Research Fellowship - Cancer Council's Beat Cancer project
- State Government through the Department of Health
- Australian Government through the Medical Research Future Fund
- National Institutes of Health's National Center for Advancing Translational Sciences grant [L1TUR002494]
- Astellas
- National Health and Medical Research Council of Australia [1121057] Funding Source: NHMRC
Endocrine therapies for prostate cancer often lead to the reactivation of the androgen receptor, promoting disease progression. This study shows that the transcription factor KLF5 is induced during treatment, promoting cellular migration and the development of a basal epithelial cell phenotype.
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 Kruppel-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. While many treatments for prostate cancer suppress the androgen receptor it becomes reactivated during disease progression. Here, the authors show that a KLF5 transcriptional programme is also activated during treatment and promotes migration and the appearance of a basal cell phenotype.
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