Department of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, Minnesota, United States of America.
PLoS One. 2013 May 6;8(5):e60664. doi: 10.1371/journal.pone.0060664. Print 2013.
For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors.
对于晚期前列腺癌（CaP），肿瘤向化疗耐药状态的进展以及对化疗耐药机制的了解不足是该疾病治疗的主要障碍。在这里，我们提供了令人信服的证据，表明 BMI1 多梳蛋白和干细胞因子在决定肿瘤对化疗的命运方面起着至关重要的作用。我们表明，在人类 CaP 疾病的进展过程中，BMI1 的水平逐渐增加。我们表明，富含 BMI1 的肿瘤细胞对化疗无反应，而沉默 BMI1 的肿瘤细胞对治疗有反应。通过使用微阵列、ChIP、免疫印迹和荧光素酶报告基因分析，我们确定了一种独特的机制，通过该机制，BMI1 可使肿瘤细胞免受化疗的影响。我们发现 BMI1 调节（i）TCF4 转录因子的活性和（ii）TCF4 与抗凋亡 BCL2 基因启动子区域的结合。值得注意的是，在表现出高 BMI1 水平的前列腺组织中观察到 TCF4 对 BCL2 基因的占有率增加。使用除 CaP 以外的肿瘤细胞，我们还表明，BMI1 调节的 TCF4 介导的 BCL2 是普遍的。值得注意的是，观察到强制表达 BMI1 可使正常细胞向过度增殖模式驱动。我们表明，针对 BMI1 可改善动物模型中携带化疗耐药前列腺肿瘤的多西紫杉醇治疗效果。我们建议，BMI1 可以作为治疗化疗耐药肿瘤的潜在分子靶标。
