Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer

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.

Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer

“…We also found that the enza plus sara combination further reduced AR mRNA expression with little induction of NR3C1 and NR3C2 expression, hinting towards sara preventing this mechanism of resistance. We also observed that sara altered AR gene signature activity in both the Dehm (31) and Nelson (32) AR-regulated gene sets. In the Dehm gene set, which contains 19 AR-regulated genes, we found that sara treatment alone reduced certain ARregulated genes (e.g.…”

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer

“…ETV4 mediates dosage-dependent prostate tumor initiation and promotes metastasis of prostate adenocarcinoma in response to PI3K and RAS co-activation [43]. KLF5 opposes AR activities and drives the double-negative PC phenotype [26, 44]. TFAP2A activation indicates emergence of neural crest lineages [25].…”

P-Glycoprotein and Androgen Receptor Expression Reveals Independence of Canine Prostate Cancer from Androgen Hormone Stimulation

“…In human PC, tumors generally express ARs and respond to androgen deprivation therapy [2]. Only one set of tumors became resistant to androgen deprivation and required additional aggressive treatment [26]. Nevertheless, canine PC appears to originate under low testosterone stimulation and negative to low AR expression [13,19,27].…”