Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression.
Cancer cells metabolize glucose at elevated rates and have a higher sensitivity to glucose reduction. However, the precise molecular mechanisms leading to different responses to glucose restriction between normal and cancer cells are not fully understood. We analyzed normal WI-38 and immortalized WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells. Moreover, in WI-38/S cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16(INK4a). Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction. The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as antiaging approaches.
Li
Yuanyuan
Y
Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Liu
Liang
L
Tollefsbol
Trygve O
TO
D031204:Caloric Restriction; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019098:Telomerase; D005947:Glucose