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.

Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6 ^−/− mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.

Luminal breast cancers are typically estrogen receptor–positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.Significance: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202–17. ©2016 AACR.See related commentary by Sears and Gray, p. 131.This article is highlighted in the In This Issue feature, p. 115