The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Zhou, Wenhui; Ni, Thomas K.; Wronski, Ania; Glass, Benjamin; Skibinski, Adam; Beck, Andrew H.; Kuperwasser, Charlotte

doi:10.1016/j.celrep.2016.10.006

Cited by 88 publications

(87 citation statements)

References 71 publications

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“…However, the detailed regulatory mechanisms for these two molecules in different tissues remain to be investigated. Slug reportedly undergoes acetylation-dependent protein degradation, and the deacetylase SIRT2 was identified as a key mediator of this posttranslational mechanism [53]. These findings are in agreement with the notion that Slug is a labile protein that is subjected to delicate regulation by multiple signaling pathways to control its ubiquitylation and degradation.…”

Section: Discussionsupporting

confidence: 76%

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells

Liu

Shi

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Slug protein, a transcription factor for the induction of epithelial-mesenchymal transition (EMT) and cancer cell invasion and metastasis, is frequently upregulated in human epithelial cancers. However, mutation of this gene in cancer is rare, and the mechanism of its dysregulation remains unknown, especially in head and neck squamous cell carcinoma (HNSCC). Methods: We examined the role of TNF-α in the stabilization of Slug by immunoprecipitation-westernblot analysis. Migration of HNSCC cells with or without knockdown of Slug gene expression was assayed by a wound healing assay. Immunohistochemical staining analysis was used to measurement Slug levels in both normal and HNSCC tumor tissues. Results: The inflammatory cytokine TNF-α stabilized Slug protein by inhibiting its ubiquitination through the NF-κB pathway. Inhibition of NF-κB or knockdown of p65 abrogated the TNF-α-induced stabilization of Slug. Knockdown of Slug expression inhibited cancer cell migration and EMT characteristics induced by TNF-α. Moreover, increased levels of Slug were found to correlate with lymph node metastasis and predict poor prognosis in patients with HNSCC. Conclusions: NF-κB-mediated stabilization of Slug underlies the inflammation-induced EMT and metastasis in HNSCC, which may serve as a therapeutic target for metastatic HNSCC.

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Section: Discussionsupporting

confidence: 76%

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells

Liu

Shi

Wang

et al. 2018

Cell Physiol Biochem

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“…There are seven sirtuin members in mammals, sirtuin 1–7 (SIRT1–7), and these exhibit diverse functions, including transcriptional silencing, metabolic regulation, and apoptosis. SIRT2 is localized to both the nucleus and the cytoplasm and deacetylates α‐tubulin, FOXO1, FOXO3a, p300, Lys16 of histone H4, Slug, CDH1, CDC20, and p53 . SIRT2 also deacetylates the transcriptional repressor Slug to prevent its degradation and thereby controls malignancy of basal‐like breast cancer .…”

Section: Introductionmentioning

confidence: 99%

“…SIRT2 is localized to both the nucleus and the cytoplasm [8][9][10][11] and deacetylates a-tubulin, FOXO1, FOXO3a, p300, Lys16 of histone H4, Slug, CDH1, CDC20, and p53 [8][9][10][11][12][13]. SIRT2 also deacetylates the transcriptional repressor Slug to prevent its degradation and thereby controls malignancy of basal-like breast cancer [11]. Furthermore, a SIRT2-specific inhibitor, a thiomyristoyl lysine compound, promotes c-Myc ubiquitination and degradation and exhibits broad anticancer activity [14].…”

Section: Introductionmentioning

confidence: 99%

SIRT 2‐mediated inactivation of p73 is required for glioblastoma tumorigenicity

et al. 2018

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Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells, including glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C-terminal lysine residues. Our results suggest that SIRT2-mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of glioblastoma.

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“…It has been reported that SIRT2, as a strong deacetylase [23][24][25][26], is highly expressed in the brain and is markedly associated with aging [27,28]; additionally, SIRT2 was evaluated in the brains of PD patients, suggesting a potential role in PD development [29]. It has been confirmed that selective inhibitors of SIRT2 can protect against α-syn-mediated toxicity and dopaminergic cell death, both in vitro and in a Drosophila model of PD [19].…”

Section: Discussionmentioning

confidence: 94%

miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

Wang

Cai

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increasing evidence suggests the important role of sirtuin 2 (SIRT2) in the pathology of Parkinson’s disease (PD). However, the association between potential functional polymorphisms in the SIRT2 gene and PD still needs to be identified. Exploring the molecular mechanism underlying this potential association could also provide novel insights into the pathogenesis of this disorder. Methods: Bioinformatics analysis and screening were first performed to find potential microRNAs (miRNAs) that could target the SIRT2 gene, and molecular biology experiments were carried out to further identify the regulation between miRNA and SIRT2 and characterize the pivotal role of miRNA in PD models. Moreover, a clinical case-control study was performed with 304 PD patients and 312 healthy controls from the Chinese Han population to identify the possible association of single nucleotide polymorphisms (SNPs) within the miRNA binding sites of SIRT2 with the risk of PD. Results: Here, we demonstrate that miR-486-3p binds to the 3’ UTR of SIRT2 and influences the translation of SIRT2. MiR-486-3p mimics can decrease the level of SIRT2 and reduce a-synuclein (α-syn)-induced aggregation and toxicity, which may contribute to the progression of PD. Interestingly, we find that a SNP, rs2241703, may disrupt miR-486-3p binding sites in the 3’ UTR of SIRT2, subsequently influencing the translation of SIRT2. Through the clinical case-control study, we further verify that rs2241703 is associated with PD risk in the Chinese Han population. Conclusion: The present study confirms that the rs2241703 polymorphism in the SIRT2 gene is associated with PD in the Chinese Han population, provides the potential mechanism of the susceptibility locus in determining PD risk and reveals a potential target of miRNA for the treatment and prevention of PD.

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The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Cited by 88 publications

References 71 publications

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells

Stabilization of Slug by NF-κB is Essential for TNF-α -Induced Migration and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Cells

SIRT 2‐mediated inactivation of p73 is required for glioblastoma tumorigenicity

miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

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