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MPND Loss Epigenetically Activates TGFβ/SMAD3 Signaling to Drive Tumor Progression and Metastasis in Non-Small Cell
Jianfeng Yu1,2, Jieru Zhang1,3, Jun Zhang4
1Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, China.
Cancer Research
|May 27, 2026
Summary
The Mpr1/Pad1 N-terminal domain-containing protein (MPND) deubiquitinase is downregulated in non-small cell lung cancer (NSCLC). Loss of MPND promotes tumor growth and metastasis by activating the TGF-β/SMAD3 pathway.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a prevalent malignancy with limited treatment options.
- Understanding NSCLC tumorigenesis requires elucidating its underlying molecular mechanisms.
Purpose of the Study:
- To investigate the role of the deubiquitinase MPND in NSCLC progression.
- To identify the molecular pathways regulated by MPND in NSCLC.
Main Methods:
- Analysis of MPND expression in NSCLC tissues and correlation with clinical outcomes.
- Functional assays assessing cell migration, invasion, and cancer stem cell characteristics upon MPND depletion.
- Biochemical assays to determine MPND's interaction with histones and its effect on histone ubiquitination.
- Investigation of MPND's impact on gene transcription and signaling pathways, including TGF-β/SMAD3.
- Validation in mouse tumor models and human NSCLC samples.
Main Results:
- MPND is frequently deleted and downregulated in NSCLC, correlating with poor prognosis.
- MPND depletion enhances NSCLC cell migration, invasion, and stemness.
- MPND removes ubiquitin from H2A K119ub and H2B K120ub, influencing chromatin architecture.
- Loss of MPND activates the TGF-β/SMAD3 pathway, promoting tumor growth and metastasis.
Conclusions:
- MPND acts as a tumor suppressor in NSCLC through epigenetic regulation.
- The MPND-epigenetic-TGF-β/SMAD3 axis is a critical pathway in NSCLC progression.
- Targeting the TGF-β/SMAD3 pathway may be a therapeutic strategy for MPND-deficient NSCLC.
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