Acetylation-Dependent Regulation of Skp2 Function

Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration. [Display omitted] ► Skp2 is acetylated by p300 at K68 and K71 within the nuclear localization signal ► SIRT3 interacts with and deacetylates Skp2 ► Acetylation stabilizes Skp2 and promotes its cytoplasmic localization ► Skp2 promotes cell migration through regulation of E-cadherin degradation Acetylation of the E3 ubiquitin ligase Skp2 leads to its cytoplasmic retention. This enhances the ubiquitin-mediated destruction of the adhesion molecule E-cadherin, thereby promoting cell migration during tumorigenesis.