Androgen receptor variants: RNA-based mechanisms and therapeutic targets.
Androgen receptor variants: RNA-based mechanisms and therapeutic targets.
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雄激素受体变体：基于 RNA 的机制和治疗靶点。
DOI：
10.1093/hmg/ddaa089
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发表时间：
2020-05
影响因子：
3.5
通讯作者：
Kiel T Tietz;S. Dehm
中科院分区：
文献类型：
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作者：
Kiel T Tietz;S. Dehm
前列腺癌是美国男性癌症死亡的第二大原因。雄激素受体（AR）转录因子是前列腺中正常腺体稳态以及前列腺癌细胞生长和存活的主要调节因子。因此，AR靶向治疗可有效改善手术或放疗无法治愈的晚期前列腺癌患者的总生存期。然而，前列腺癌将不可避免地在AR靶向治疗中进展为去势抵抗性前列腺癌（CRPC）表型，这几乎是所有前列腺癌特异性死亡的原因。AR基因的mRNA转录变体在CRPC细胞中表达，并且可以被翻译以产生AR变体（AR-V）蛋白，其作为配体非依赖性、组成型活性转录因子起作用。AR-V能够通过促进通常被AR靶向疗法抑制的AR靶基因的表达来支持CRPC细胞的生长。关于控制AR-V表达的机制的知识是不完整的。研究表明，AR基因的基因组重排是某些CRPC肿瘤中不同AR-V表达的基础，但转录后过程代表了CRPC中AR-V表达的更广泛调控机制。本文综述了选择性剪接、3'末端加工和miRNA介导的AR和AR-V表达的mRNA抑制，以及这些机制作为CRPC治疗靶点的潜力。
Prostate cancer is the second leading cause of male cancer death in the United States. The androgen receptor (AR) transcription factor is a master regulator of normal glandular homeostasis in the prostate, as well as growth and survival of prostate cancer cells. Therefore, AR-targeted therapies are effective for improving overall survival of patients with advanced prostate cancer that is incurable by surgery or radiation. However, prostate cancer will inevitably progress on AR-targeted therapies to a castration-resistant prostate cancer (CRPC) phenotype that accounts for virtually all prostate cancer-specific death. mRNA transcript variants of the AR gene are expressed in CRPC cells, and can be translated to produce AR variant (AR-V) proteins that function as ligand-independent, constitutively active transcription factors. AR-Vs are able to support growth of CRPC cells by promoting expression of AR target genes that are normally suppressed by AR-targeted therapies. Knowledge of mechanisms that govern expression of AR-Vs is incomplete. Studies have shown genomic rearrangements of the AR gene underlie expression of diverse AR-Vs in certain CRPC tumors, but post-transcriptional processes represent a broader regulatory mechanism for expression of AR-Vs in CRPC. This review focuses on alternative splicing, 3' end processing, and miRNA-mediated mRNA repression of AR and AR-V expression, and the potential these mechanisms hold as therapeutic targets for CRPC.