Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer. Academic Article uri icon

Overview

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.

authors

publication date

  • November 4, 2021

Research

keywords

  • Kruppel-Like Transcription Factors
  • Neuroendocrine Cells
  • Prostatic Neoplasms, Castration-Resistant
  • Receptor, ErbB-2
  • Receptors, Androgen

Identity

PubMed Central ID

  • PMC8568894

Scopus Document Identifier

  • 85118616251

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2014.08.016

PubMed ID

  • 34737261

Additional Document Info

volume

  • 12

issue

  • 1