Investigating the mechanism of tricyclic decyl benzoxazole -induced apoptosis in liver Cancer cells through p300-mediated FOXO3 activation.

OBJECTIVE: To investigate whether tricyclic decylbenzoxazole (TDB) regulates liver cancer cell proliferation and apoptosis through p300-mediated FOXO acetylation. METHODS: Sequencing, adenovirus, and lentivirus transfection were performed in human liver cancer cell line SMMC-7721 and apoptosis was detected by Tunel, Hoechst, and flow cytometry. TEM for mitochondrial morphology, MTT for cell proliferation ability, Western blot, and PCR were used to detect protein levels and mRNA changes. RESULTS: Sequencing analysis and cell experiments confirmed that TDB can promote the up-regulation of FOXO3 expression. TDB induced FOXO3 up-regulation in a dose-dependent manner, promoted the expression of p300 and Bim, and enhanced the acetylation and dephosphorylation of FOXO3, thus promoting apoptosis. p300 promotes apoptosis of cancer cells through Bim and other proteins, while HAT enhances the phosphorylation of FOXO3 and inhibits apoptosis. Overexpression of FOXO3 can increase the expression of exo-apoptotic pathways (FasL, TRAIL), endo-apoptotic pathways (Bim), and acetylation at the protein level and inhibit cell proliferation and apoptotic ability, while FOXO3 silencing or p300 mutation can partially reverse apoptosis. In tumor tissues with overexpression of FOXO3, TDB intervention can further increase the expression of p53 and caspase-9 proteins in tumor cells, resulting in loss of mitochondrial membrane integrity during apoptosis, the release of cytoplasm during signal transduction, activation of caspase-9 and synergistic inhibition of growth. CONCLUSION: TDB induces proliferation inhibition and promotes apoptosis of SMMC-7721 cells by activating p300-mediated FOXO3 acetylation.

MEIS1 and its potential as a cancer therapeutic target (Review).

Meis homeobox 1 (Meis1) was initially discovered in 1995 as a factor involved in leukemia in an animal model. Subsequently, 2 years later, MEIS1, the human homolog, was cloned in the liver and cerebellum, and was found to be highly expressed in myeloid leukemia cells. The MEIS1 gene, located on chromosome 2p14, encodes a 390­amino acid protein with six domains. The expression of homeobox protein MEIS1 is affected by cell type, age and environmental conditions, as well as the pathological state. Certain types of modifications of MEIS1 and its protein interaction with homeobox or pre­B­cell leukemia homeobox proteins have been described. As a transcription factor, MEIS1 protein is involved in cell proliferation in leukemia and some solid tumors. The present review article discusses the molecular biology, modifications, protein­protein interactions, as well as the role of MEIS1 in cell proliferation of cancer cells and MEIS1 inhibitors. It is suggested by the available literature MEIS1 has potential to become a cancer therapeutic target.