title: The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer.
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.
authors: Department of Developmental, Chemical, and Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors: Wenhui
authors: W
authors: Zhou
authors: Department of Developmental, Chemical, and Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors: Thomas K
authors: TK
authors: Ni
authors: Department of Developmental, Chemical, and Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors: Ania
authors: A
authors: Wronski
authors: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, EC/CLS-633B, Boston, MA 02215, USA.
authors: Benjamin
authors: B
authors: Glass
authors: Department of Developmental, Chemical, and Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors: Adam
authors: A
authors: Skibinski
authors: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, EC/CLS-633B, Boston, MA 02215, USA.
authors: Andrew
authors: A
authors: Beck
authors: Department of Developmental, Chemical, and Molecular Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA. Electronic address: charlotte.kuperwasser@tufts.edu.
authors: Charlotte
authors: C
authors: Kuperwasser
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D055550:Protein Stability; D040901:Proteomics; D056565:Sirtuin 2 / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000071250:Snail Family Transcription Factors; D056565:Sirtuin 2; D008239:Lysine
keywords: SIRT2; Slug; acetylation; basal-like breast cancer; deacetylase; protein stability; sirtinol; triple-negative breast cancer