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Transcriptional activation of PPP1R14C by KLF7 unleashes CDK1 activity to promote lung squamous cell carcinoma
Lihua Xing1, Chunluan Yuan2, Xiaozhu Shen3
1Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China.
Abstract:
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.
Insights
Protein Phosphatase 1 Regulatory Subunit 14C (PPP1R14C) drives lung squamous cell carcinoma (LUSC) by inhibiting PP1, leading to CDK1 hyperactivation. Targeting this pathway offers a new therapeutic strategy for LUSC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Lung squamous cell carcinoma (LUSC) lacks targeted therapies, necessitating identification of new molecular drivers.
- Protein Phosphatase 1 Regulatory Subunit 14C (PPP1R14C) is an endogenous inhibitor of Protein Phosphatase 1 (PP1).
Purpose of the Study:
- To identify novel oncogenic drivers in LUSC.
- To elucidate the role of PPP1R14C in LUSC pathogenesis.
- To explore the KLF7-PPP1R14C-PP1-CDK1 signaling pathway as a therapeutic target.
Main Methods:
- Integrative multi-omics analyses to assess PPP1R14C expression in LUSC.
- ChIP assays to determine KLF7 binding to the PPP1R14C promoter.
- Co-immunoprecipitation to study PPP1R14C-PP1 interaction.
- In vitro and in vivo assays to evaluate the functional role of PPP1R14C and CDK1 inhibition.
Main Results:
- PPP1R14C is significantly overexpressed in LUSC, correlating with advanced stage and poor survival.
- KLF7 directly drives PPP1R14C expression.
- PPP1R14C inhibits PP1, leading to sustained CDK1 hyperactivation, promoting LUSC cell proliferation, invasion, and tumorigenesis.
- Pharmacological inhibition of CDK1 reverses PPP1R14C-mediated oncogenic phenotypes.
Conclusions:
- A novel KLF7-PPP1R14C-PP1-CDK1 signaling axis is critical for LUSC pathogenesis.
- PPP1R14C acts as a pivotal oncogenic driver in LUSC.
- PPP1R14C is a potential prognostic biomarker and a promising therapeutic target for LUSC.
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