Gene expression profilings for prostate cancer cells after inhibition of PARP1 or PARP2 using pharmaceutical or siRNA-based approaches

Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated transcription provides new opportunities for therapeutic intervention. We have previously discovered that a genetic variant in one of the DNA repair genes, PARP2, is associated with aggressive PCa. Here, we show that a high expression level of PARP2 in PCa tumors is associated with high Gleason scores and biochemical recurrence using The Cancer Genome Atlas (TCGA) dataset. Functional studies reveal that PARP2 enhances AR-mediated gene expression through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to the enhancer regions genome-wide in PCa cells. Selective targeting of PARP2, but not PARP1, by genetic or pharmacological means blocks interaction between PARP2 and FOXA1, which in turn attenuates AR-mediated transcription and inhibits AR-positive PCa growth. SIGNIFICANCE: Current anti-androgens act through blocking ligand binding or inhibiting androgen synthesis. Selective targeting of PARP2 may provide a novel therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA repair defect status and, more importantly, when direct AR-targeted therapies fail. Overall design: Gene expression by RNA-Seq of LNCaP cells treated with PARP inhibitors or after PARP1/PARP2 gene knockdown, with biological duplicates.

雄激素受体（Androgen receptor, AR）信号通路是驱动前列腺癌（prostate cancer, PCa）生长与进展的关键因素。解析AR介导的转录调控影响因素，可为治疗干预提供全新思路。本团队此前已发现，DNA修复基因之一的聚腺苷二磷酸核糖聚合酶2（PARP2）存在一处遗传变异，且该变异与侵袭性前列腺癌相关。本研究借助癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据集分析证实，前列腺癌组织中高表达的PARP2与较高的格里森评分（Gleason score）及生化复发显著相关。功能实验结果显示，PARP2可通过与先驱因子叉头框A1（FOXA1）结合，促进AR在前列腺癌细胞全基因组范围内向增强子区域的招募，从而增强AR介导的基因表达。通过遗传学或药理学手段选择性靶向PARP2（而非PARP1），可阻断PARP2与FOXA1的相互作用，进而削弱AR介导的转录过程并抑制AR阳性前列腺癌的生长。
研究意义：当前临床使用的抗雄激素疗法主要通过阻断配体结合或抑制雄激素合成发挥作用。选择性靶向PARP2可通过破坏FOXA1的功能实现AR抑制，为前列腺癌治疗提供全新策略；该疗法或可惠及所有患者，无论其是否存在DNA修复缺陷，更为重要的是，当直接靶向AR的疗法失效时，该策略仍可发挥效用。
整体实验设计：对经PARP抑制剂处理或经PARP1/PARP2基因敲低的LNCaP细胞进行RNA测序（RNA-Seq）基因表达分析，设置生物学重复两组。