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Potent androgen receptor inhibition unleashes oncogenic action of the KLF5 stem cell transcription factor in castration-resistant prostate cancer [RNA-seq]

ABSTRACT: Advanced prostate cancer (PC) can be treated with endocrine therapies that inhibit transcriptional activity of the androgen receptor (AR). However, PC will ultimately evolve under the selection pressure of these therapies and progress to a lethal phenotype termed castration-resistant PC (CRPC). Recent studies suggest that de-differentiation away from an AR-driven luminal cell identity may be a key, early step. However, early therapy-induced mechanisms of prostate cancer cell de-differentiation are poorly understood. Here we show that the stem cell transcription factor Kruppel-like factor 5 (KLF5) is transcriptionally repressed by AR, and de-repressed by enzalutamide. KLF5 expression is high in a subset of CRPC tissues, but low in primary adenocarcinoma. KLF5 functioned as oncogene in CPRC cells, promoting cellular migration, anchorage-independent growth, expression of basal cell markers, and transcriptional signatures of CRPC lineage plasticity, but had modest effects on cell proliferation. Chromatin immuno-precipitation (ChIP)-sequencing, RNA-sequencing, and co-immunoprecipitation experiments established a physical interaction between KLF5 and AR, and integrative analysis revealed that KLF5 and AR drive opposing transcriptional programs. We identified ERBB2 as a point of transcriptional convergence that was activated by KLF5 and repressed by AR. Accordingly, KLF5 expression levels in CRPC tissues correlated with predicted sensitivity to the dual EGFR inhibitor lapatanib, and the ERBB2-specific inhibitor mubritinib blocked KLF5-driven cell migration. Collectively, these findings implicate KLF5 as an AR-suppressed oncogene that drives early steps in CRPC de-differentiation and disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148806 | GEO | 2021/09/21

REPOSITORIES: GEO

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Project description:Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LNCaP prostate cancer (PC) cell line, one overexpressing AR 2M-bM-^@M-^S3-fold and the other 4M-bM-^@M-^S5-fold compared with the control cells. We used chromatin immunoprecipitation (ChIP) and deep-sequencing (seq) to identify AR-binding sites (ARBSs). We found that the number of ARBSs and the AR-binding strength were positively associated with the level of AR when cells were stimulated with low concentrations of androgens. In cells overexpressing AR, the chromatin binding of the receptor took place in 100-fold lower concentration of the ligand than in control cells. We conM-oM-,M-^Armed the association of AR level and chromatin binding in two PC xenografts, one containing AR gene ampliM-oM-,M-^Acation with high AR expression, and the other with low expression. By combining the ChIP-seq and expression proM-oM-,M-^Aling, we identiM-oM-,M-^Aed AR target genes that are upregulated in PC. Of them, the expression of ZWINT, SKP2 (S-phase kinase-associated protein 2 (p45)) and FEN1 (M-oM-,M-^Bap structure-speciM-oM-,M-^Ac endonuclease 1) was demonstrated to be increased in CRPC, while the expression of SNAI2 was decreased in both PC and CRPC. FEN1 protein expression was also associated with poor prognosis in prostatectomy-treated patients. Finally, the knock-down of FEN1 with small interfering RNA inhibited the growth of LNCaP cells. Our data demonstrate that the overexpression of AR sensitizes the receptor binding to chromatin, thus, explaining how AR signaling pathway is reactivated in CRPC cells. Examination of AR binding with 9 cell line samples + control and 2 xenograft samples + control. ChIPseq with AR antibody in 3 different LNCaP derivative cell lines overexpressing AR upon treatment with different androgen concentrations and 2 different tumor xenografts expressing different AR levels.

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Potent androgen receptor inhibition unleashes oncogenic action of the KLF5 stem cell transcription factor in castration-resistant prostate cancer [RNA-seq]

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