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. Here, 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 (CSC)-like characteristics in NSCLC cells. Mechanistically, MPND interacted with histones, removing the ubiquitin moiety from monoubiquitinated histone H2A K119 (H2A K119ub) 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 TGF-β/SMAD3 signaling pathway. Specifically, knockout of MPND increased H2B K120ub and chromatin accessibility at the SMAD3 locus, facilitating transcriptional activation. In mouse tumor models and clinical samples from NSCLC patients, loss of MPND consistently triggered activation of the TGF-β/SMAD3 axis, thereby promoting tumor growth and metastasis. Together, these data reveal an epigenetic pathway underlying NSCLC progression and suggest that targeting the TGF-β/SMAD3 axis may be particularly effective for the treatment of the MPND-deficient NSCLC tumors.
Yu et al. (Wed,) studied this question.