Abstract
Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here, we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.
Highlights
Over the past decade, large-scale genomic profiling has revealed the molecular landscape of breast cancers (Perou et al, 2000; van’t Veer et al, 2002), identifying discrete subtypes as well as underlying driver genes
To determine whether Slug repressor activity is affected by the changes in Slug protein levels mediated by SIRT2, we examined the expression of Slug target genes following SIRT2 perturbation
Slug failed to co-immunoprecipitate with SIRT1, indicating a specific interaction with SIRT2 (Figure S2C). Consistent with these findings, dual-immunofluorescence (IF) staining of endogenous Slug and SIRT2 proteins revealed their nuclear co-localization in MCF10A cells (Figure 3B). These results show that SIRT2 physically interacts with Slug protein, suggesting that Slug may be a substrate for the enzymatic activity of the deacetylase SIRT2
Summary
Wenhui Zhou, Thomas K. Ni, Ania Wronski, Benjamin Glass, Adam Skibinski, Andrew Beck, Charlotte Kuperwasser Zhou et al show that the deacetylase SIRT2 inhibits acetylation-dependent degradation of Slug protein. In breast cancer, frequent SIRT2 overexpression extends Slug stability, conferring aggressive, basal-like malignant features and growth. Zhou et al, 2016, Cell Reports 17, 1302–1317 October 25, 2016 a 2016 The Authors. http://dx.doi.org/10.1016/j.celrep.2016.10.006
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
