Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.

致命性前列腺癌（PCa）的特征是存在转移和对治疗产生耐药性。转移瘤是在动态细胞骨架重塑的多步骤过程中形成的。肌动蛋白细胞骨架调节基因CALD1编码蛋白质 caldesmon (CaD)。其亚型低分子量 CaD (l-CaD) 在非肌肉细胞中发挥作用，支持参与力产生和机械传感的细丝的功能。包括糖皮质激素受体 (GR) 在内的多种因子已被确定为不同细胞类型中 l-CaD 的调节因子，但 l-CaD 在 PCa 中的调节尚未明确。PCa 通过多种策略对雄激素信号传导进行治疗性抑制，从而产生耐药性。已知的策略包括改变雄激素受体（AR）、改变类固醇合成以及绕过AR信号传导，例如通过GR上调。在这里，我们报告体外下调 l-CaD 可促进上皮表型并减少 3D 球体生长，这在体内反映在斑马鱼 PCa 异种移植物中转移形成的减少。因此，CALD1 mRNA 表达与 PCa 患者的上皮间质转化 (EMT) 转录物相关。我们还表明，CALD1在多个 PCa 数据集中与GR高度共表达，并且 GR 激活在体外上调 l-CaD。此外，在 PCa 异种移植小鼠模型中出现抗雄激素治疗耐药性后，GR 上调与 l-CaD 表达增加相关。总之，GR 调节的 l-CaD 在形成 PCa 转移中发挥作用，当通过 GR 上调绕过 AR 信号传导而获得抗雄激素抵抗时，其具有临床相关性。