Transcriptional activation of PPP1R14C by KLF7 unleashes CDK1 activity to promote lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is a lethal malignancy with a stark lack of targeted therapies, demanding the identification of novel molecular drivers. Here, we identify Protein Phosphatase 1 Regulatory Subunit 14C (PPP1R14C), an endogenous inhibitor of Protein Phosphatase 1 (PP1), as a pivotal oncogenic driver in LUSC. Integrative multi-omics analyses revealed consistent PPP1R14C overexpression in LUSC, which correlated with advanced tumor stage and poor patient survival. Mechanistically, we establish that the transcription factor KLF7 directly binds the PPP1R14C promoter to drive its expression. We demonstrate that PPP1R14C executes its pro-tumorigenic function by physically interacting with and inhibiting the PP1 catalytic subunit, thereby preventing the dephosphorylation and inactivation of CDK1. This sustained CDK1 hyperactivation fuels LUSC cell proliferation, invasion, and in vivo tumorigenesis. Critically, pharmacological inhibition of CDK1 completely abrogates the oncogenic phenotypes conferred by PPP1R14C. Our findings delineate a novel and actionable KLF7-PPP1R14C-PP1-CDK1 signaling cascade essential for LUSC pathogenesis, positioning PPP1R14C as both a prognostic biomarker and a compelling therapeutic target.