Epigenetic regulation of SMAD3 by histone methyltransferase SMYD2 promotes lung cancer metastasis

초록

Lung cancer: An opportunity to prevent cancer spreadA protein that accelerates cancer spread (metastasis) could be an effective target for novel therapies for non-small-cell lung cancer (NSCLC), which generally has a poor prognosis. Increased activity of the SMYD2 protein is associated with more aggressive growth in several cancer types, and Kwangho Kim of the Korea Research Institute of Bioscience and Biotechnology, Daejeon, and colleagues have linked heightened SMYD2 expression with poor prognosis in NSCLC patients. Experiments with cultured lung cancer cells demonstrated that SMYD2 plays a role in epithelial-mesenchymal transition, a cellular transformation process that leads to metastatic growth. Interventions that disrupt SMYD2 production in tumor cells hindered this process. Mice transplanted with SMYD2-deficient cells were significantly less prone to metastases than animals receiving cells with unimpeded SMYD2 production. These findings could present a therapeutic approach for this form of lung cancer. Epigenetic alterations, especially histone methylation, are key factors in cell migration and invasion in cancer metastasis. However, in lung cancer metastasis, the mechanism by which histone methylation regulates metastasis has not been fully elucidated. Here, we found that the histone methyltransferase SMYD2 is overexpressed in lung cancer and that knockdown of SMYD2 could reduce the rates of cell migration and invasion in lung cancer cell lines via direct downregulation of SMAD3 via SMYD2-mediated epigenetic regulation. Furthermore, using an in vitro epithelial-mesenchymal transition (EMT) system with a Transwell system, we generated highly invasive H1299 (In-H1299) cell lines and observed the suppression of metastatic features by SMYD2 knockdown. Finally, two types of in vivo studies revealed that the formation of metastatic tumors by shSMYD2 was significantly suppressed. Thus, we suggest that SMYD2 is a potential metastasis regulator and that the development of SMYD2-specific inhibitors may help to increase the efficacy of lung cancer treatment.

키워드