Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical School, Rochester, NY, United States.
Department of Animal Science, College of Agriculture and Natural Resources, Michigan State University, Lansing, MI, United States.
Steroids. 2019 Nov;151:108463. doi: 10.1016/j.steroids.2019.108463. Epub 2019 Jul 22.
Paxillin is extensively involved in focal adhesion signaling and kinase signaling throughout the plasma membrane and cytoplasm. However, recent studies in prostate cancer suggest that paxillin also plays a critical role in regulating gene expression within the nucleus, serving as a liaison between cytoplasmic and nuclear MAPK and Androgen Receptor (AR) signaling. Here we used RNA-seq to examine the paxillin-regulated transcriptome in several human prostate cancer cell lines. First, we examined paxillin effects on androgen-mediated transcription in control or paxillin-depleted AR-positive LNCaP and C4-2 human prostate cancer cells. In androgen-dependent LNCaP cells, we found over 1000 paxillin-dependent androgen-responsive genes, some of which are involved in endocrine therapy resistance. Most paxillin-dependent AR-mediated genes in LNCaP cells were no longer paxillin-dependent in androgen-sensitive, castration-resistant C4-2 cells, suggesting that castration-resistance may markedly alter paxillin effects on genomic AR signaling. To examine the paxillin-regulated transcriptome in the absence of androgen signaling, we performed RNA-seq in AR-negative PC3 human prostate cancer cells. Paxillin enhanced several pro-proliferative pathways, including the CyclinD/Rb/E2F and DNA replication/repair pathways. Additionally, paxillin suppressed pro-apoptotic genes, including CASP1 and TNFSF10. Quantitative PCR confirmed that these pathways are similarly regulated by paxillin in LNCaP and C4-2 cells. Functional studies showed that, while paxillin stimulated cell proliferation, it had minimum effect on apoptosis. Thus, paxillin appears to be an important transcriptional regulator in prostate cancer, and analysis of its transcriptome might lead to novel approaches toward the diagnosis and treatment of this important disease.
整联蛋白广泛参与整个质膜和细胞质中的粘着斑信号和激酶信号。然而，最近前列腺癌的研究表明，整联蛋白在调节核内基因表达方面也起着关键作用，充当细胞质和核 MAPK 和雄激素受体 (AR) 信号之间的联络。在这里，我们使用 RNA-seq 检查了几种人前列腺癌细胞系中整联蛋白调节的转录组。首先，我们检查了整联蛋白对雄激素介导的转录的影响在对照或整联蛋白耗竭的 AR 阳性 LNCaP 和 C4-2 人前列腺癌细胞中。在雄激素依赖性 LNCaP 细胞中，我们发现超过 1000 个整联蛋白依赖的雄激素反应基因，其中一些与内分泌治疗耐药有关。大多数在 LNCaP 细胞中依赖整联蛋白的 AR 介导的基因在雄激素敏感的去势抵抗 C4-2 细胞中不再依赖整联蛋白，这表明去势抵抗可能显著改变整联蛋白对基因组 AR 信号的影响。为了在没有雄激素信号的情况下检查整联蛋白调节的转录组，我们在 AR 阴性 PC3 人前列腺癌细胞中进行了 RNA-seq。整联蛋白增强了几个促增殖途径，包括 CyclinD/Rb/E2F 和 DNA 复制/修复途径。此外，整联蛋白抑制了促凋亡基因，包括 CASP1 和 TNFSF10。定量 PCR 证实这些途径在 LNCaP 和 C4-2 细胞中也受整联蛋白的类似调节。功能研究表明，尽管整联蛋白刺激细胞增殖，但对细胞凋亡的影响最小。因此，整联蛋白似乎是前列腺癌中的一个重要转录调节剂，对其转录组的分析可能为这种重要疾病的诊断和治疗提供新的方法。
