Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.
Nat Commun
; 12(1): 6377, 2021 11 04.
Article
em En
| MEDLINE
| ID: mdl-34737261
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores Androgênicos
/
Receptor ErbB-2
/
Fatores de Transcrição Kruppel-Like
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Células Neuroendócrinas
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Neoplasias de Próstata Resistentes à Castração
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article