PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma. PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma

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 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. Overall design: RNA-sequencing (RNA-seq) in control and PML silenced RCC4 cells.

透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）是肾细胞癌（renal cell carcinoma, RCC）的主要亚型，确诊时常已处于晚期或转移阶段，5年无病生存率仅为13%。野生型p53蛋白的功能失活与ccRCC的治疗耐药密切相关，但p53功能异常的具体分子机制仍未得到充分阐明。因此，亟需进一步阐明疾病进展与治疗耐药的相关机制。本研究首次报道了ccRCC对早幼粒细胞白血病蛋白（promyelocytic leukemia protein, PML）存在新型的非致癌基因成瘾性依赖。研究发现，PML在ccRCC中呈高表达状态，敲低PML可抑制细胞增殖，并在体内减轻间变性疾病的病理特征。从机制上来说，PML缺失可激活p53依赖的细胞衰老通路，由此揭示了一条全新的调控轴，可在ccRCC中抑制p53活性与细胞衰老。经美国食品药品监督管理局（Food and Drug Administration, FDA）批准的PML抑制剂三氧化二砷处理可诱导PML降解与p53积累，并在体外与体内抑制ccRCC的增殖扩张。综上，本研究通过明确ccRCC对PML基因的非致癌基因成瘾性，揭示了一种全新的ccRCC易感靶点，并为重新利用已获批的药理学干预手段以恢复p53功能与化疗敏感性奠定了理论基础。实验整体设计：对对照组与PML沉默的RCC4细胞进行RNA测序（RNA-sequencing, RNA-seq）分析。