Cucurbitacin B alters the expression of tumor-related genes by epigenetic modifications in NSCLC and inhibits NNK-induced lung tumorigenesis
Menée sur des lignées cellulaires de cancer du poumon non à petites cellules et à l'aide d'un modèle murin, cette étude montre que la cucurbitacine B, un triterpène tétracyclique d'origine végétale, modifie, via des mécanismes épigénétiques, l'expression de gènes impliqués dans la régulation de la prolifération ou de la croissance des cellules tumorales et inhibe la tumorigenèse induite chimiquement
Non-small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMTs) and histone deacetylase (HDACs) inhibitors is effective against various cancers including lung cancer. However, optimizing the synergistic dose regime is very difficult and involves adverse side effects. Therefore, in this study, we have shown that cucurbitacin B (CuB), a single bioactive triterpenoid compound, inhibits both DNMTs and HDACs starting at a very low dose of 60 nM in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSGs) such as p21CIP1/WAF1 and p16INK4A as well as downregulation of oncogenes c-MYC and K-RAS and key tumor promoter gene (TPG), human telomerase reverse transcriptase (hTERT). The upregulation of TSGs and downregulation of TPG were consistently correlated with the alterations in their promoter methylation and histone modifications. This altered expression of TPG and TSGs is, at least in part, responsible for the inhibition of cellular proliferation and induction of cellular apoptosis in NSCLC. Further, CuB treatment significantly inhibited the tumor incidence and multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, which was associated with the induction of apoptosis and inhibition of hyperproliferation in the lung tissues. Together, our study provides new insight into the CuB-mediated epigenetic alterations and its chemotherapeutic effects on lung cancer.