ZDHHC11-Mediated Palmitoylation of PPM1A Regulates Lung Cancer Metastasis via the TGF-β1-Smad2/3 Signaling Pathway.

Authors

Yulong Li, Yu Zhou, Peng Zhao, Min Shi, Zhiyan Wang, Zhijian Zhang, Geping Qu

Published in

American journal of respiratory cell and molecular biology. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Lung cancer remains the most common cause of cancer-related mortality worldwide. The transforming growth factor-beta 1 (TGF-β1) pathway promotes epithelial-mesenchymal transition (EMT), invasion, and metastasis in advanced disease via mothers against decapentaplegic homolog 2 (Smad2) and Smad3. This study investigated how post-translational modifications regulate TGF-β1-Smad signaling.
Lung cancer cell lines and a mouse metastasis model were used to explore the roles of protein phosphatase magnesium-dependent 1A (PPM1A) palmitoylation, zinc finger DHHC-type palmitoyltransferase 11 (ZDHHC11), and ubiquitin-specific peptidase 5 (USP5) in regulating Smad2/3 signaling. Palmitoylation-deficient and wild-type PPM1A constructs were introduced by lentiviral transduction. Protein levels, modifications, and interactions were analyzed by western blot, immunoprecipitation, and immunofluorescence. Palmitoylation was measured using acyl-resin-assisted capture (Acyl-RAC). Cell invasion and migration were assessed using Transwell assays.
Palmitoylation of PPM1A at cysteine 71 enhanced the interaction between PPM1A and Smad2/3, promoted Smad2/3 dephosphorylation, and suppressed lung cancer cell invasion and metastasis. ZDHHC11 was identified as the enzyme responsible for PPM1A palmitoylation; its loss diminished this modification and accelerated metastasis in vivo. TGF-β1 downregulated ZDHHC11 expression, weakened PPM1A-Smad2/3 binding, and increased cell migration. Additionally, USP5 stabilized Smad2/3 by preventing their ubiquitin-mediated degradation, and TGF-β1 further amplified this effect by limiting PPM1A access.
This study identified a novel palmitoylation-dependent mechanism regulating TGF-β1-Smad signaling in lung cancer. Upregulating the ZDHHC11-PPM1A axis or targeting USP5 may offer new strategies to inhibit metastasis in lung cancer.

PMID:
42573527
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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