Abstract
Enzalutamide is a second-generation anti-androgen for treatment of castration-resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR-eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide-resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy.
Highlights
Prostate cancer (PC) remains the most commonly diagnosed cancer and is the second leading cause of cancer deaths in American men [1]
These results indicate that enzalutamide was cytotoxic to LNCaP cells, but cytostatic to C4-2 castration-resistant prostate cancer (CRPC) cells following shortterm treatment
LNCaP cells are sensitive, but C4-2 CRPC cells are resistant to long-term treatment with enzalutamide
Summary
Prostate cancer (PC) remains the most commonly diagnosed cancer and is the second leading cause of cancer deaths in American men [1]. Recent studies suggest that extra-gonadal androgen, including PC cell intracrine mechanism, can still activate the AR pathway even at a very low concentration [3,4,5]. These seminal findings have led to the development of the secondgeneration hormonal therapies including enzalutamide. Administration of enzalutamide to CRPC patients has www.impactjournals.com/oncotarget achieved a prolonged overall survival [7], yet a proportion of patients do not benefit from this treatment. Expression of genes involved in the androgen synthesis, such as AKR1C3, HSD3B and CYP17A1, was significantly elevated in enzalutamide-resistant PC cells [9].
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