KDM4B-mediated AP2A1-K217 demethylation promotes immune evasion and anti-PD-1 therapy resistance in renal cell carcinoma

Abstract

The role of non-histone lysine methylation in tumorigenesis has attracted increasing attention, and the dysregulated “writers”, “erasers” and “readers” of it are promising therapeutic targets. In this study, we demonstrated that lysine-specific demethylase 4B (KDM4B) was significantly upregulated in renal cell carcinoma (RCC), with high expression correlating with poor prognosis and immune checkpoint blockade (ICB) resistance. Multiple in vitro and in vivo functional experiments demonstrated that KDM4B promotes the proliferation and angiogenesis of RCC cells. Additionally, suppressing tumor-intrinsic KDM4B expression enhances intratumoral CD8 + T cell functionality and reduces their exhaustion marker levels. Mechanistically, in addition to its well-studied histone demethylase activity, KDM4B also modulates non-histone demethylation to promote tumor progression and immunosuppression. Specifically, KDM4B demethylates non-histone AP2A1 at Lys217 to promote its interaction with AP2B1, a process that thereby enhances AP2 complex assembly. In turn, this promotes clathrin-mediated TGF-β receptor endocytosis and TGF-β-SMAD2/3 pathway activation, ultimately upregulating TGF-β1 transcription to drive tumor progression and immunosuppression. Inhibiting KDM4B enhances the therapeutic efficacy of PD-1 blockade therapy in the RCC patient-derived xenograft (PDX) models. Collectively, KDM4B plays a crucial role in promoting the progression and immune evasion of RCC, and targeting KDM4B may be a novel strategy to enhance the response of RCC to immunotherapy.