Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Advanced Technology Core, Alkek Center for Molecular Discovery.
Endocrinology. 2021 Mar 1;162(3). doi: 10.1210/endocr/bqaa227.
Androgen receptor (AR) signaling continues to drive castration-resistant prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT). Constitutively active shorter variants of AR, lacking the ligand binding domain, are frequently expressed in CRPC and have emerged as a potential mechanism for prostate cancer to escape ADT. ARv7 and ARv567es are 2 of the most commonly detected variants of AR in clinical samples of advanced, metastatic prostate cancer. It is not clear if variants of AR merely act as weaker substitutes for AR or can mediate unique isoform-specific activities different from AR. In this study, we employed LNCaP prostate cancer cell lines with inducible expression of ARv7 or ARv567es to delineate similarities and differences in transcriptomics, metabolomics, and lipidomics resulting from the activation of AR, ARv7, or ARv567es. While the majority of target genes were similarly regulated by the action of all 3 isoforms, we found a clear difference in transcriptomic activities of AR versus the variants, and a few differences between ARv7 and ARv567es. Some of the target gene regulation by AR isoforms was similar in the VCaP background as well. Differences in downstream activities of AR isoforms were also evident from comparison of the metabolome and lipidome in an LNCaP model. Overall our study implies that shorter variants of AR are capable of mediating unique downstream activities different from AR and some of these are isoform specific.
雄激素受体（AR）信号通路在去势治疗（ADT）后仍然驱动去势抵抗性前列腺癌（CRPC）的进展。缺乏配体结合域的 AR 短变异体持续活跃，在 CRPC 中频繁表达，并已成为前列腺癌逃避 ADT 的潜在机制。ARv7 和 ARv567es 是在晚期转移性前列腺癌的临床样本中最常检测到的两种 AR 变异体。目前尚不清楚 AR 变异体是否仅仅作为 AR 的较弱替代品起作用，或者是否可以介导与 AR 不同的独特同种型特异性活性。在这项研究中，我们使用可诱导表达 ARv7 或 ARv567es 的 LNCaP 前列腺癌细胞系，以描绘 AR、ARv7 或 ARv567es 激活导致的转录组学、代谢组学和脂质组学的相似性和差异。虽然大多数靶基因的调控方式相似，但我们发现 AR 与变异体之间的转录组学活性存在明显差异，ARv7 和 ARv567es 之间也存在一些差异。在 VCaP 背景下，一些 AR 同种型调节的靶基因也存在相似性。在 LNCaP 模型中对代谢组学和脂质组学的比较也表明，AR 同种型的下游活性存在差异。总的来说，我们的研究表明，AR 的短变异体能够介导与 AR 不同的独特下游活性，其中一些是同种型特异性的。
