Abstract
Non-small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) 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 nmol/L in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSG) such as CDKN1A and CDKN2A, 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. Furthermore, 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.
Highlights
Lung cancer is the leading cause of cancer-related mortality worldwide, with nearly 1.4 million deaths each year [1]
We found slightly decreased mRNA expressions of these tumor suppressor genes (TSG) at 600 nmol/L as compared with 60 nmol/L cucurbitacin B (CuB) concentrations, which might be due to the mRNA instability as well as higher rate of protein turnover observed in case of cell-cycle regulators [26, 27]
As we found that the treatment of H1299 cells with CuB inhibited the expression of DNA methyltransferase (DNMT), we further investigated the consequence of their inhibition at the extent of global as well as gene-specific promoter methylation
Summary
Lung cancer is the leading cause of cancer-related mortality worldwide, with nearly 1.4 million deaths each year [1]. Non– small cell lung cancers (NSCLC) constitute almost 85% of total diagnosed cases and are caused mainly due to the exposure to the environmental carcinogens. The early stages of lung tumorigenesis involve reversible promoter methylation and histone modification changes [2]. Bioactive natural compounds can be defined as the natural compounds that can exhibit a biological activity on the living cells. These compounds possess the capability to reverse the epigenetic alterations. Bioactive natural compounds have been shown to restore the expressions of to tumor
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