Search

DACT2, a tumor suppressor gene in various tumors, is frequently down-regulated via hypermethylation. We found DACT2 gene expressions were dramatically silenced ( P  = 0.002, n = 8) in our clinical colorectal cancer (CRC) tissues, and TCGA data revealed DACT2 hypermethylation correlated to CRC poor prognosis ( P  = 0.0129, HR = 0.2153, n = 248). Thus, by screening twelve nutritional compounds, we aimed to find out an effective DACT2 epigenetic stimulator to determine whether DACT2 epigenetic restoration could reverse CRC tumorigenesis. We found that kaempferol significantly increased DACT2 expressions up to 3.47-fold in three CRC cells (HCT116, HT29, and YB5). Furthermore, kaempferol remarkably decreased DACT2 methylation (range: 19.58%-67.00%, P <  0.01), while increased unmethylated DACT2 by 13.72-fold ( P <  0.01) via directly binding to DNA methyltransferases DNMT1. By epigenetic reactivating DACT2 transcription, kaempferol notably inhibited nuclear β-catenin expression to inactivate Wnt/β-catenin pathway, which consequently restricted CRC cells proliferation and migration. Moreover, in AOM/DSS-induced CRC tumorigenesis, kaempferol-demethylated DACT2 effectively decreased tumor load (range: 50.00%-73.52%, P <  0.05). By determining the chemopreventive and chemotherapeutic efficacy of a novel DACT2 demethylating stimulator, we demonstrated that DACT2 epigenetic restoration could successfully slow down and reverse CRC tumorigenesis. [ABSTRACT FROM AUTHOR]

Histone modifications play critical roles in the progression of non-small cell lung cancer (NSCLC), which accounts for almost 85% of all diagnosed lung cancers. Magnolol and polyphenol mixture (PM) derived from Magnolia officinalis exhibited remarkable antitumor activities in lung cancer. However, the epigenetic effects and molecular mechanisms of magnolol and PM in NSCLC have yet to be reported. In this study, the epigenetic effects of magnolol and PM in NSCLC were examined in vitro and in vivo . Results revealed that magnolol and PM significantly suppressed the expression levels and function of class I histone deacetylases (HDACs). In A549 and H1299 cells, magnolol and PM remarkably induced cell apoptosis by arresting the cell cycle in the G0/G1 phase while simultaneously activating various pro-apoptotic signals, including TRAIL-R2 (DR5), Bax, caspase 3, cleaved caspase 3, and cleaved PARP. However, these apoptosis-promoting effects could be attenuated by TSA, which is a specific class I HDACs inhibitor. ChIP assays also demonstrated that magnolol and PM significantly enriched the histone acetyl mark (H3K27ac) in the promoter region of DR5. In A549 xenograft model, magnolol and PM notably reduced tumor growth by 44.40% and 35.40%, respectively. Therefore, magnolol and PM, as potential inhibitors of class I HDACs, induced tumor cell apoptosis and suppressed tumor growth partially by epigenetically activating DR5, which is a key protein in death receptor signaling pathway. [ABSTRACT FROM AUTHOR]