A role for Sirtuins 1 and 2 in the activation of the dishevelled-TIAM 1-RAC1 axis in cancer cells.

摘要

A classic regulator of embryonic development and differentiation, the Wnt signaling pathway has an incontrovertible role in tumorigenesis. Over three decades of unrelenting research have described a well defined signal transduction mechanism for the canonical and the non-canonical Wnt pathways. However, development of targeted therapies against the pathway activity in cancer has lagged behind.;Classically studied as cytosolic scaffolds, DVL proteins have a newly described role in the nucleus in regulating expression of a handful of Wnt-target genes. To identify potential DVL-target genes I utilized genome-wide expression profiling upon DVL knockdown in cancer cells. Validation of DVL-binding on gene promoters, in combination with the knowledge that SIRT1/2 regulate DVL protein levels, will open avenues for investigating the role of DVLs in regulating gene expression.;Overall, this study demonstrates that targeting enzymatic activity of SIRT1 and/or SIRT2 in cancer cells inhibits the non-canonical Wnt pathway at the level of DVL or downstream of it. Thus, developing targeted therapy against SIRT1/2 could provide a novel course for targeting Wnt signaling in cancer.;In a previously published report we identified class Ill histone deacetylases, the sirtuin proteins, as positive regulators of the Wnt signaling pathway. SIRT (silent information regulator) 1 and 2, are overexpressed in human cancers and have been shown to promote tumorigenesis. In this study I elucidated a novel role for SIRT1 and S1RT2 in the non-canonical Wnt pathway in cancer cells, where these proteins positively regulated active Racl-GTPase levels and cell migration. To decipher the mechanistic details of this observation, I studied the effect of inhibition of the deacetylase activity or depletion of SIRT1/2 proteins on a Rac guanine-nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (TIAM1). The results demonstrated that TIAM1 was an acetylated protein and binding of SIRT1/2 maintained it in a deacetylated state in cancer cells. At a functional level, S1RT1/2 inhibition or depletion decreased TIAM1 exchange activity, inhibited its membrane localization and disrupted its binding to DVL1, possibly decreasing Rac1 activation. Finally, specific loss of SIRT1 protein also suggested, as a possibility, that increased acetyiation of TIAM1 targeted it for degradation by the proteasomal pathway.