p53-PA200 反馈回路调控年龄依赖性肿瘤发生机制

Abstract

Tumor incidence increases markedly with advancing age, yet the molecular mechanisms linking aging-driven senescence to tumorigenesis remain incompletely understood. The proteasome activator PA200 preserves genomic stability by mediating the degradation of acetylated histones during aging. However, its function in age-associated tumor progression is poorly defined. Here, we demonstrate that PA200 promotes aging-associated tumorigenesis independent of its histone-degrading activity. Elevated PA200 correlates with poor prognosis and advancing age in human lung cancer. PA200-deficient tumor cells exhibit suppressed proliferation and migration, accompanied by aggravated oxidative-stress-triggered cellular senescence. Mechanistically, p53 directly binds and repressesPSME4transcription at its promoter. Reciprocally, PA200 facilitates proteasomal degradation of β-catenin, thereby sustaining p53 activity and forming a negative feedback loop. In the urethane-induced mouse lung tumor model, PA200 ablation markedly reduces tumor burden, especially in middle-aged mice. This effect is coupled with β-catenin accumulation, lowered p53 levels, and partial remodeling of the pro-inflammatory tumor microenvironment. Our findings uncover the p53-PA200-β-catenin feedback axis as a key driver of age-dependent lung tumorigenesis and highlight PA200 as a potential therapeutic target for elderly patients with lung cancer.