Laboratory of Cancer and Apoptosis, Department of Biological Chemistry, School of Scences, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
Mol Cancer Res. 2011 Aug;9(8):1078-90. doi: 10.1158/1541-7786.MCR-11-0155. Epub 2011 Jun 23.
BRCA1 plays numerous roles in the regulation of genome integrity and chemoresistance. Although BRCA1 interaction with key proteins involved in DNA repair is well known, its role as a coregulator in the transcriptional response to DNA damage remains poorly understood. In this study, we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. BRCA1 expression mediates apoptosis, cell-cycle arrest, and decreased viability in response to doxorubicin treatment. Xenograft studies using human prostate carcinoma PC3 cells show that BRCA1 depletion results in increased tumor growth. A focused survey of BRCA1-regulated genes in prostate carcinoma reveals that multiple regulators of genome stability and cell-cycle control, including BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, and GADD153, are direct transcriptional targets of BRCA1. Furthermore, we show that BRCA1 targets GADD153 promoter to increase its transcription in response to DNA damage. Finally, GADD153 depletion significantly abrogates BRCA1 influence on cell-cycle progression and cell death in response to doxorubicin treatment. These findings define a novel transcriptional pathway through which BRCA1 orchestrates cell fate decisions in response to genotoxic insults, and suggest that BRCA1 status should be considered for new chemotherapeutic treatment strategies in prostate cancer.
BRCA1 在基因组完整性和化学抗性的调节中发挥多种作用。虽然 BRCA1 与参与 DNA 修复的关键蛋白的相互作用是众所周知的，但它作为 DNA 损伤转录反应的核心调节剂的作用仍知之甚少。在这项研究中，我们表明 BRCA1 在前列腺癌对遗传毒性应激的转录反应中发挥核心作用。BRCA1 的表达介导了多柔比星治疗时的细胞凋亡、细胞周期停滞和活力下降。使用人前列腺癌细胞 PC3 的异种移植研究表明，BRCA1 的耗竭导致肿瘤生长增加。对前列腺癌中 BRCA1 调节基因的集中调查显示，基因组稳定性和细胞周期控制的多个调节剂，包括 BLM、FEN1、DDB2、H3F3B、BRCA2、CCNB2、MAD2L1 和 GADD153，是 BRCA1 的直接转录靶标。此外，我们表明 BRCA1 靶向 GADD153 启动子以增加其在 DNA 损伤后的转录。最后，GADD153 的耗竭显著削弱了 BRCA1 对多柔比星治疗时细胞周期进程和细胞死亡的影响。这些发现定义了一个新的转录途径，通过该途径，BRCA1 协调细胞命运决策以应对遗传毒性损伤，并表明在前列腺癌的新化疗治疗策略中应考虑 BRCA1 状态。
