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 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.The promyelocytic leukemia protein (PML) is essential to sustain clear cell renal cell carcinoma (ccRCC) expansion via p53 inhibition and the PML-targeting drug arsenic trioxide exerts cancer inhibitory functions in ccRCC.PML is overexpressed and efficiently partitioned into PML-NBs in ccRCC. PML inhibition blocks ccRCC expansion in vitro and in vivo. Targeting ccRCC non-oncogenic addiction to PML via gene silencing or arsenic trioxide unleashes p53-dependent growth arrest and apoptosis. Arsenic trioxide is effective at inhibiting expansion of ccRCC cells with wild type and mutant p53.The promyelocytic leukemia protein (PML) is essential to sustain clear cell renal cell carcinoma (ccRCC) expansion via p53 inhibition and the PML-targeting drug arsenic trioxide exerts cancer inhibitory functions in ccRCC.