Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34737261.
- Also identified by DOI 10.1038/s41467-021-26612-1 and PMC identifier 8568894.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Kruppel-Like Transcription Factors
- Neuroendocrine Cells
- Prostatic Neoplasms, Castration-Resistant
- Erb-b2 Receptor Tyrosine Kinases
- Receptors, Androgen