Role of SIRT6 in Metabolic Reprogramming During Colorectal Carcinoma.

摘要

During the research period stated above, we have expanded our colony of SIRT6 F/F; Villin- Cre; APCmin mice and found that lack of SIRT6 dramatically increases intestinal tumorigenesis in vivo, and this phenotype is driven by an enhanced aerobic glycolysis in the absence of SIRT6. To study in more detail how SIRT6 (and aerobic glycolysis) modulates intestinal tumorigenesis, we have knocked-down SIRT6 in a panel of human CRC cell lines (HCT116, SW620, HT29, SW1116). However, no differences in glycolytic metabolism were found. Alternatively, we have taken advantage of our mouse model and found that lack of SIRT6 leads to an increase in the number of intestinal stem cells (ISC), suggesting that SIRT6 regulates intestinal tumorigenesis by controlling the number of tumor initiating cells. We have confirmed this result by using intestinal organoids derived from our mouse model. In parallel, we generated a SIRT6 F/F, Lgr5-EGFP-Cre; APCmin mouse line to precisely address the role of SIRT6 in the ISCs. Our preliminary data shows that SIRT6 F/F, Lgr5-EGFP-Cre; APCmin mice have increased numbers of ISCs compared to control animals, suggesting that SIRT6 might regulate ISC.