RESUMEN
Advanced prostate cancer initially responds to androgen deprivation therapy (ADT), but the disease inevitably recurs as castration-resistant prostate cancer (CRPC). Although CRPC initially responds to abiraterone and enzalutamide, the disease invariably becomes nonresponsive to these agents. Novel approaches are required to circumvent resistance pathways and to extend survival, but the mechanisms underlying resistance remain poorly defined. Our group previously showed the histone lysine-N-methyltransferase EZH2 to be overexpressed in prostate cancer and quantitatively associated with progression and poor prognosis. In this study, we screened a library of epigenetic inhibitors for their ability to render CRPC cells sensitive to enzalutamide and found that EZH2 inhibitors specifically potentiated enzalutamide-mediated inhibition of proliferation. Moreover, we identified antisense oligonucleotides (ASO) as a novel drug strategy to ablate EZH2 and androgen receptor (AR) expression, which may have advantageous properties in certain settings. RNA-seq, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin using sequencing demonstrated that EZH2 inhibition altered the AR cistrome to significantly upregulate AR signaling, suggesting an enhanced dependence of CRPC cells on this pathway following inhibition of EZH2. Combination treatment with ASO targeting EZH2 and AR transcripts inhibited prostate cancer cell growth in vitro and in vivo better than single agents. In sum, this study identifies EZH2 as a critical epigenetic regulator of ADT resistance and defines ASO-based cotargeting of EZH2 and AR as a promising strategy for the treatment of CRPC.Significance: Simultaneous targeting of lysine methyltransferase EZH2 and the AR with ASO proves a novel and effective therapeutic strategy in patients with CRPC. Cancer Res; 78(20); 5731-40. ©2018 AACR.
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Epigénesis Genética , Oligonucleótidos Antisentido/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Antagonistas de Andrógenos/farmacología , Androstenos/farmacología , Animales , Benzamidas , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante de Neoplasias , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Pronóstico , Receptores Androgénicos/metabolismo , Transducción de SeñalRESUMEN
The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.
Asunto(s)
Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Receptores Androgénicos/genética , Andrógenos/genética , Andrógenos/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Próstata/fisiología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Largo no Codificante/metabolismo , Receptores Androgénicos/metabolismo , Transducción de SeñalRESUMEN
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.