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.

中文翻译：

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PML 抑制透明细胞肾细胞癌中 p53 活性和细胞衰老。


透明细胞肾细胞癌 (ccRCC) 是 RCC 的主要亚型，经常在晚期/转移期被诊断出来，5 年无病生存率为 13%。野生型 p53 蛋白的功能失活与 ccRCC 治疗耐药有关，但 p53 功能障碍的详细机制仍不清楚。因此，需要更好地了解疾病进展和治疗抵抗的机制。在这里，我们报告了一种新的 ccRCC 对早幼粒细胞白血病 (PML) 蛋白的依赖性。我们发现 PML 在 ccRCC 中过度表达，并且 PML 耗竭可抑制细胞增殖并减轻体内再生性疾病的病理特征。从机制上讲，PML 丢失释放了 p53 依赖性细胞衰老，从而描绘了限制 ccRCC 中 p53 活性和衰老的新调控轴。使用 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 扩张。因此，通过定义 PML 基因的非癌基因成瘾，我们的工作揭示了一种新的 ccRCC 脆弱性，并为重新利用可用的药物干预措施以恢复 p53 功能和化疗敏感性奠定了基础。