Abstract 2651: Nuclear prothymosin α suppresses TGF-β-induced EMT by stabilizing smad7: implications for lung cancer progression and metastasis

Elevated expression of prothymosin α (ProTα), a 12.5-kDa acidic protein encoded by the PTMA gene, is frequently observed in cancers, including lung cancer, where it correlates with poor prognosis. Although ProTα is primarily localized to the nucleus, advanced-stage tumors exhibit its translocation to the cytoplasm, indicating a potential involvement in disease progression. In this study, we aim to elucidate the molecular mechanisms by which nuclear ProTα regulates epithelial-to-mesenchymal transition (EMT) and metastasis in lung cancer. Our findings demonstrate that nuclear ProTα suppresses TGF-β-induced EMT by enhancing Smad7 acetylation and stability. This acetylation disrupts the binding of Smad2 to the promoters of EMT transcription factors SNAI1, TWIST1, and ZEB1, thereby reducing their expression. Conversely, the loss of nuclear ProTα resulting from caspase-3-mediated cleavage of its nuclear localization signal (NLS) enables cytoplasmic translocation, associated with increased metastatic potential. Moreover, the use of mutant Smad7 constructs confirmed that the inhibitory effect of ProTα on EMT is dependent on Smad7 acetylation. Our clinical analyses of lung cancer specimens demonstrate that high nuclear ProTα levels are prevalent in early-stage tumors, while metastatic cases exhibit significant nuclear ProTα loss. These observations identify nuclear ProTα as a potential biomarker for tumor progression and a suppressor of lung cancer metastasis through TGF-β signaling interruption. In conclusion, this study underscores the importance of nuclear ProTα in lung cancer progression and highlights its potential as a prognostic indicator and therapeutic target for metastasis prevention. Further research into ProTα-targeted therapies could open new avenues in cancer treatment. Citation Format: Bing-Hua Su, Li-Hsin Cheng. Nuclear prothymosin α suppresses TGF-β-induced EMT by stabilizing smad7: implications for lung cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2651.