ArticleCancer research2026
MPND Loss Epigenetically Activates TGFβ/SMAD3 Signaling to Drive Tumor Progression and Metastasis in Non-Small Cell Lung Cancer.
Article in Cancer research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Although non-small cell lung cancer (NSCLC) is among the most prevalent malignancies, currently available treatments remain largely ineffective, highlighting the need to elucidate the precise mechanisms of tumorigenesis. The Mpr1/Pad1 N-terminal domain-containing protein (MPND) is a member of the JAMM family of deubiquitinases. In this study, we found that MPND is frequently deleted, and its expression is significantly downregulated in NSCLC tumor tissues. Low MPND levels correlated with poor clinical outcomes, and depletion of MPND enhanced cell migration, invasion, and cancer stem cell-like characteristics in NSCLC cells. Mechanistically, MPND interacted with histones, removing the ubiquitin moiety from monoubiquitinated histone H2A K119 and H2B K120 (H2B K120ub). Loss of MPND elevated the ubiquitination marks, leading to alterations in chromatin architecture. Furthermore, MPND modulated gene transcription, and its depletion activated the transforming growth factor-beta (TGFβ)/SMAD3 signaling pathway. Specifically, the knockout of MPND increased H2B K120ub and chromatin accessibility at the SMAD3 locus, facilitating transcriptional activation. In mouse tumor models and clinical samples from patients with NSCLC, the loss of MPND consistently triggered activation of the TGFβ/SMAD3 axis, thereby promoting tumor growth and metastasis. Together, these data reveal an epigenetic pathway underlying NSCLC progression and suggest that targeting the TGFβ/SMAD3 axis may be particularly effective for the treatment of MPND-deficient NSCLC tumors. SIGNIFICANCE: Loss of MPND in lung cancer promotes tumor growth and metastasis by increasing histone ubiquitination to epigenetically activate TGFβ/SMAD3 signaling, suggesting that targeting this axis may provide therapeutic benefit in MPND-deficient tumors.
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