Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
Sci Rep. 2017 Mar 3;7:42795. doi: 10.1038/srep42795.
Castration-resistance prostate cancer (CRPC), also known as hormone-refractory prostate cancer (HRPC), requires immediate attention since it is not only resistant to androgen ablation, chemo- and radiotherapy, but also highly metastatic. Increasing evidence suggests that enrichment of neuroendocrine (NE) cells is associated with CRPC. Here, combined RNA-seq and ChIP-seq analysis reveals that REST is involved in epithelial-mesenchymal transition (EMT) and stemness acquisition in NE differentiated prostate cancer (PCa) cells via direct transcriptional repression of Twist1 and CD44. Specifically we show that short-term knockdown of REST induces NE differentiation of LNCaP cells. Long-term REST knockdown enhanced the expression of Twist1 and CD44, cell migration and sphere formation. Overexpression of REST in hormone-refractory CWR22Rv1 PCa cells significantly reduces Twist1 and CD44 expression, cell migration and sphere formation. Collectively, our study uncovers REST in regulating EMT and stemness properties of NE PCa cells and suggests that REST is a potential therapeutic target for CRPC.
去势抵抗性前列腺癌（CRPC），也称为激素难治性前列腺癌（HRPC），由于不仅对雄激素剥夺、化疗和放疗有抗性，而且还具有高度转移性，因此需要立即关注。越来越多的证据表明，神经内分泌（NE）细胞的富集与 CRPC 有关。在这里，联合 RNA-seq 和 ChIP-seq 分析表明，REST 通过直接转录抑制 Twist1 和 CD44，参与 NE 分化的前列腺癌细胞中的上皮-间充质转化（EMT）和干性获得。具体来说，我们表明短期敲低 REST 诱导 LNCaP 细胞的 NE 分化。长期 REST 敲低增强了 Twist1 和 CD44 的表达、细胞迁移和球体形成。在激素难治性 CWR22Rv1 PCa 细胞中转染过量的 REST 显著降低了 Twist1 和 CD44 的表达、细胞迁移和球体形成。总的来说，我们的研究揭示了 REST 在调节 NE PCa 细胞的 EMT 和干性特性中的作用，并表明 REST 是 CRPC 的一个潜在治疗靶点。
