Cortactin binds
F-actin and promotes cell migration. We showed earlier that
cortactin is acetylated. Here, we identify
SIRT1 (a class III
histone deacetylase) as a
cortactin deacetylase and p300 as a
cortactin acetylase. We show that
SIRT1 deacetylates
cortactin in vivo and in vitro and that the
SIRT1 inhibitor
EX-527 increases amounts of acetylated
cortactin in
ovarian cancer cells. We also show that p300 acetylates
cortactin in vivo and that cells lacking or depleted of p300 express less-acetylated
cortactin than do control cells. Deletion analysis mapped the SIRT1-binding domain of
cortactin to its repeat region, which also binds
F-actin. Mouse embryo fibroblasts (MEFs) lacking sir2alpha (the mouse homolog of
SIRT1) migrated more slowly than did wild-type cells. The expression of
SIRT1 in sir2alpha-null cells restored migratory capacity, as did expression of a deacetylation-mimetic mutant of
cortactin.
SIRT1 and
cortactin were more abundant in
breast tumor tissue than in their normal counterparts, whereas
SIRT1 expression inversely correlates with the ratio of acetylation
cortactin versus total
cortactin. These data suggest that deacetylation of
cortactin is associated with high levels of
SIRT1 and
tumorigenesis. Finally, breast and
ovarian cancer cell lines expressing an acetylation mimetic mutant of
cortactin are less motile than that of control cells, whereas cells expressing the deacetylation mimetic mutant of
cortactin migrate faster than that of control cells in Transwell migration assays. In summary, our results suggest that
cortactin is a novel substrate for
SIRT1 and p300 and, for the first time, a possible role for
SIRT1 in cell motility through deacetylation of
cortactin.