Rac1-GTPases serve as intermediary cellular switches, which conduct transient and constitutive signals from upstream cues, including those from Ras
oncoproteins. Although the sirtuin1 (
SIRT1) deacetylase is overexpressed in several human
cancers and has recently been linked to
cancer cell motility as a context-dependent regulator of multiple pathways, its role in Rac1 activation has not been reported. Similarly,
SIRT2 has been demonstrated to be upregulated in some
cancers; however, studies have also reported its role in
tumor suppression. Here, we demonstrate that
SIRT1 and
SIRT2 positively regulate the levels of Rac1-GTP and the activity of
T-cell lymphoma invasion and
metastasis 1 (TIAM1), a Rac
guanine nucleotide exchange factor (GEF). Transient inhibition of
SIRT1 and
SIRT2 resulted in increased acetylation of TIAM1, whereas chronic
SIRT2 knockdown resulted in enhanced acetylation of TIAM1.
SIRT1 regulates Dishevelled (DVL)
protein levels in
cancer cells, and DVL along with TIAM1 are known to augment Rac activation; however,
SIRT1 or 2 has not been previously linked with TIAM1. We found that diminished
sirtuin activity led to the disruption of the DVL1-TIAM1 interaction. We hence propose a model for Rac activation where
SIRT1/2 positively modulates the DVL/TIAM1/Rac axis and promotes sustained pathway activation.