Deacetylation of cortactin by SIRT1 promotes cell migration

Abstract

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 lessacetylated 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 sir2a (the mouse homolog of SIRT1) migrated more slowly than did wildtype cells. The expression of SIRT1 in sir2a-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.

Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

“…It has been reported that the cellular role of CTTN is related to membrane dynamics and cortical actin assembly (Lua and Low, 2005 (Kinley et al, 2003). Zhang et al (2009) reported that deacetylation of CTTN promotes cell migration of breast and ovarian cancer. In this study, fluorescently labeled phalloidin staining showed that the assembled F-actin decreased in CRT-siRNA cells as compared with non-silencing siRNA and parental ESCC cells.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…In 2007, Zhang and collaborators identified an F-actin binding protein, cortactin, as a new target for acetylation. Cortactin acetylation is regulated through different factors (PCAF, p300, HDAC6, and SIRT1), leading to the reduction of cortactin binding to F-actin and cell mobility [189,190]. Recently, Cortactin acetylation was also shown to affect dendritic spine morphogenesis, promoting the dendritic clustering of PSD95 and Shank1, two post-synaptic proteins, in excitatory hippocampal synapses.…”

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

“…In humans, several types of cancer, including prostate (6,7), breast cancer (8,9), colon (10,11), glioblastoma (12), lymphoma (13) and acute myeloid leukemia (14) have been demonstrated to have a significantly increased expression of SIRT1. Furthermore, a recent study showed that SIRT1 regulates the DNA damage signaling pathway through deacetylation of NBS1 to promote cellular survival (15).…”