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Title: Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

Author
item FEI, WANG - Children'S Nutrition Research Center (CNRC)
item CHAN, CHIA-SHIN - Md Anderson Cancer Center
item CHEN, KE YUN - Children'S Nutrition Research Center (CNRC)
item GUAN, XINFU - Children'S Nutrition Research Center (CNRC)
item LIN, HUI-KUAN - Md Anderson Cancer Center
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Oncogene
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/7/2011
Publication Date: 7/7/2011
Citation: Fei, W., Chan, C., Chen, K., Guan, X., Lin, H., Tong, Q. 2011. Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene. 31:1546-1557.

Interpretive Summary: The FOXO3 protein functions as a tumor suppressor. We found two enzymes (SIRT1 and SIRT2) can bind to FOXO3 and enzymatically modify FOXO3 proteins in a special way called deacetylation. This modification allows the binding of another enzyme called Skp2 to FOXO3. Skp2 further enzymatically modifies FOXO3 proteins in a way called ubiquitination to mark FOXO3 proteins for degradation. Therefore, in cells with high expression levels of SIRT1, SIRT2 or Skp2 proteins, the level of FOXO3 protein is down-regulated. Additionally, we demonstrate that in prostate cancer cells, the higher the degree of malignancy, the higher the expression of SIRT1 and Skp2 and the lower the level of FOXO3. Suppressing either SIRT1 or Skp2 in these cells bolsters FOXO3 expression and reduces malignancy. As the expression of SIRT1, SIRT2, and FOXO3 are regulated by nutrient levels such as starvation or high-fat diet, this study uncovers a novel link between nutrition and cancer.

Technical Abstract: Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the '-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuin-induced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.