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Abstract：
Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.
摘要：
透明细胞肾细胞癌（ccRCC），碾压混凝土的主要亚型，经常在晚期/转移阶段诊断，5年无病生存率为13％。野生型p53蛋白的功能性失活与ccRCC治疗抗性有关。但p53功能障碍的详细机制仍未得到充分表征。因此，需要更好地了解疾病进展和治疗抵抗的机制.这里,我们报道了一种新的ccRCC对早幼粒细胞白血病（PML）蛋白的依赖。我们显示PML在ccRCC中过表达，PML耗竭抑制细胞增殖并减轻体内间变性疾病的病理特征。机械上,PML丢失释放了p53依赖性细胞衰老，因此描绘了一种新的调节轴以限制ccRCC中的p53活性和衰老。用FDA批准的PML抑制剂三氧化二砷治疗可诱导PML降解和p53积累，并在体外和体内抑制ccRCC扩增。因此,通过定义非癌基因对PML基因的成瘾，我们的工作揭示了一个新的ccRCC易损性,并为重新利用可用的药物干预来恢复p53功能和化学敏感性奠定了基础.
