Lactylation of USP11 fosters breast cancer development by stabilizing CDK4 and activating CDK4-RB1-E2F1 pathway

Abstract

Cyclin-dependent kinase 4 (CDK4) is a key player in the cell cycle. Its frequent overexpression in a multitude of cancers correlates with increased cell proliferation and resistance to CDK4 inhibitors, highlighting the critical need to target CDK4 degradation as a therapeutic approach. However, the mechanisms governing the maintenance and homeostasis of CDK4 protein levels remain elusive. Here, we identify that deubiquitinase USP11 promotes breast cancer progression by stabilizing CDK4. Mechanistically, we demonstrate that USP11 directly interacts with CDK4 and specifically targets the Lys48-linked polyubiquitination chains at K88, K106, and K142 sites in a DUB activity-dependent manner. USP11 knockout significantly reduces CDK4 abundance, consequently inhibiting the CDK4-RB1-E2F1 pathway, cell cycle progression, and proliferation. Warburg effect-generated lactate induces lactylation of USP11 at K385 and K766 sites, which enhances its binding to CDK4. High USP11 and CDK4 expressions in breast cancer correlates with tumor progression and poor prognosis. Moreover, the co-administration of CDK4 and USP11 inhibitors exhibits synergistic efficacy in breast cancer treatment of syngeneic mouse model. This research elucidates the role of USP11 in breast cancer through the deubiquitination and stabilization of CDK4, suggesting a dual inhibitor approach as a potential therapeutic strategy.