Center for Radiological Research, Department of Radiation Oncology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
Cell Signal. 2021 Oct;86:110091. doi: 10.1016/j.cellsig.2021.110091. Epub 2021 Jul 21.
Metastatic progression is the key feature of prostate cancer primarily responsible for mortality caused by this disease. RAD9 is an oncogene for prostate cancer, and the encoded protein enhances metastasis-related phenotypes. RAD9 is a transcription factor with a limited set of regulated target genes, but the complete list of downstream genes critical for prostate carcinogenesis is unknown. We used microarray gene expression profiling and chromatin immunoprecipitation in parallel to identify genes transcriptionally controlled by RAD9 that contribute to this cancer. We found expression of 44 genes altered in human prostate cancer DU145 cells when RAD9 is knocked down by siRNA, and all of them bind RAD9 at their genomic location. FOXP1 and NDRG1 were down regulated when RAD9 expression was reduced, and we evaluated them further. We demonstrate that reduced RAD9, FOXP1 or NDGR1 expression decreases cell proliferation, rapid migration, anchorage-independent growth, anoikis resistance, and aerobic glycolysis. Ectopic expression of FOXP1 or NDRG1 partially restored aerobic glycolysis to prostate cancer cells with reduced RAD9 abundance, but only FOXP1 significantly complemented the other deficiencies. We thus show, for the first time, that RAD9 regulates FOXP1 and NDRG1 expression, and they function differently as downstream effectors for RAD9-mediated prostate cancer cell activities.
转移进展是前列腺癌的关键特征，主要负责这种疾病导致的死亡率。RAD9 是前列腺癌的癌基因，其编码的蛋白质增强了与转移相关的表型。RAD9 是一种转录因子，其受调控的靶基因有限，但对于前列腺癌发生至关重要的下游基因的完整列表尚不清楚。我们使用微阵列基因表达谱和染色质免疫沉淀平行鉴定了由 RAD9 转录控制的基因，这些基因有助于这种癌症。我们发现，当 RAD9 被 siRNA 敲低时，人前列腺癌细胞 DU145 中的 44 个基因的表达发生改变，所有这些基因在其基因组位置都与 RAD9 结合。FOXP1 和 NDRG1 的表达在 RAD9 表达降低时下调，我们进一步评估了它们。我们证明，RAD9、FOXP1 或 NDRG1 表达减少会降低细胞增殖、快速迁移、锚定独立生长、抗凋亡和有氧糖酵解。FOXP1 或 NDRG1 的异位表达部分恢复了 RAD9 丰度降低的前列腺癌细胞中的有氧糖酵解，但只有 FOXP1 显著补充了其他缺陷。因此，我们首次表明 RAD9 调节 FOXP1 和 NDRG1 的表达，它们作为 RAD9 介导的前列腺癌细胞活性的下游效应物发挥不同的作用。
