Zhou Xiaoguang, Tolstov Yanis, Arslan Aysenur, Roth Wilfried, Grüllich Carsten, Pahernik Sascha, Hohenfellner Markus, Duensing Stefan
Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
Neoplasia. 2014 Dec;16(12):1028-35. doi: 10.1016/j.neo.2014.09.012.
Resistance to DNA damage-induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC). This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage-induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA). We demonstrate that this disconnect is not caused by gene-specific repression through CCCTC-binding factor (CTCF) but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage-induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients.
对DNA损伤诱导的细胞凋亡产生抗性是癌症的一个标志，也是治疗失败和导致致命疾病结局的主要原因。肾细胞癌（RCC）是一种对包括化疗或放疗在内的DNA损伤疗法具有很大抗性的肿瘤实体。本研究旨在探索RCC中DNA损伤抗性的潜在分子机制，以制定使肿瘤细胞对DNA损伤诱导的细胞凋亡重新敏感的策略。在此，我们表明抗凋亡的RCC细胞在p53激活与下游促凋亡蛋白p53上调凋亡调节因子（PUMA）的上调之间存在脱节。我们证明这种脱节不是由CCCTC结合因子（CTCF）的基因特异性抑制引起的，而是由异常的染色质压缩引起的。发现用组蛋白去乙酰化酶（HDAC）抑制剂处理可在mRNA和蛋白质水平有效重新激活PUMA表达，并恢复对DNA损伤诱导的细胞死亡的抗性。发现PUMA的异位表达可使一组RCC细胞系对所测试的四种不同DNA损伤剂重新敏感。值得注意的是，所有分析的RCC细胞系p53均为野生型，并且敲低同样能够使RCC细胞对急性基因毒性应激敏感。综上所述，我们的结果表明RCC中的DNA损伤抗性是可逆的，涉及p53-PUMA轴，并且有可能成为改善RCC患者肿瘤学结局的靶点。
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