Acetylation Modulates SKP2 Oncogenic Signaling

The F-box protein S-phase kinase associated protein 2 (SKP2) forms part of an E3 ubiquitin ligase that regulates cell-cycle progression, and its activity can be regulated by AKT-mediated phosphorylation. Increased expression and cytoplasmic localization of SKP2 are associated with aggressive tumors and poor prognosis, suggesting that SKP2 may also participate in metastasis. Inuzuka and colleagues identify acetylation as an additional mechanism of SKP2 regulation and show that this modification positively regulates SKP2 signaling. Acetylation of SKP2 at 2 conserved lysine residues within the nuclear localization signal (NLS) was mediated by the acetyl transferase p300 and was reversed by the deacetylase Sirtuin 3, which functions as a tumor suppressor. This posttranslational modification impaired the interaction of SKP2 with CDH1, a component of the complex that triggers SKP2 proteolysis, thereby stabilizing SKP2 protein. Lysine acetylation of SKP2 within the NLS also altered its subcellular localization, resulting in cytoplasmic retention. Acetylation-mimetic mutants of SKP2 displayed increased cell-cycle progression and significantly augmented xenograft tumor growth compared with wild-type and acetylation-deficient SKP2, supporting the idea that acetylation promotes the pro-oncogenic function of SKP2. In addition, SKP2 acetylation enhanced cell migration, in part due to reduced expression of E-cadherin, an important cell adhesion protein and tumor suppressor. SKP2 protein levels were inversely correlated with E-cadherin protein abundance in both tumor cell lines and human breast cancer samples, suggesting that SKP2 directly modulates E-cadherin abundance to facilitate tumorigenesis. Consistent with this idea, SKP2 promoted the ubiquitination and proteasomal degradation of E-cadherin, and expression of a degradation-resistant form of E-cadherin resulted in decreased migration and tumor formation in vivo. Together, these findings describe a pathway that regulates SKP2-driven oncogenic signaling and suggest that SKP2 antagonists may be useful cancer therapeutics.

Inuzuka H, Gao D, Finley LWS, Yang W, Wan L, Fukushima H, et al. Acetylation-dependent regulation of Skp2 function. Cell 2012;150:179–93.