SIRT1 induces epithelial-mesenchymal transition by promoting autophagic degradation of E-cadherin in melanoma cells

Sun, Ting; Jiao, Lin; Wang, Yangxia; Yu, Yan; Ming, Liang

doi:10.1038/s41419-017-0167-4

Cited by 79 publications

(71 citation statements)

References 44 publications

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“…The fact that E-cadherin may be downregulated through the activation of autophagy has been already demonstrated on melanoma and hepatoma cells in which SIRT1 and SPHK1, respectively, regulate this process (Liu et al, 2017;Sun et al, 2018;Zhou et al, 2018). Here we went further by demonstrating that in breast cancer E-cadherin is delivered to autophagosomes.…”

Section: Discussionsupporting

confidence: 52%

The Autophagy Machinery Contributes to E-cadherin Turnover in Breast Cancer

Damiano

Spessotto

Vanin

et al. 2020

Front. Cell Dev. Biol.

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Autophagy is an intracellular catabolic process that is increasingly being recognized as a crucial factor in several human diseases including cancers. Mounting evidence suggests that autophagy allows tumor cells to overcome otherwise fatal stresses and to increase dissemination. Nevertheless, how autophagy controls these processes and in particular how it impinges on cell-cell adhesion is still poorly understood. Here, we investigate the role of autophagy in the turnover of the epithelial adhesion molecule E-cadherin in the context of breast cancer. We demonstrated in breast cancer cell lines that autophagy impinges on E-cadherin expression and in the configuration of adherens junctions. Besides, we showed that E-cadherin colocalizes with LC3B and SQSTM1/p62, two components of the autophagosome machinery. Pull down and immunoprecipitation analyses provided evidence that E-cadherin and SQSTM1/p62 physically interact. Moreover, the physical closeness of E-cadherin and SQSTM1/p62 was demonstrated by proximity ligation assays in breast cancer cell lines and primary tumors. Finally, we proved that the silencing of SQSTM1/p62 diminished the E-cadherin/LC3B colocalization, further supporting the role of SQSTM1/p62 in E-cadherin delivery to autophagosomes. These findings suggest that the activation of autophagy, reported in breast cancers with poor prognosis and in dormant breast cancer cells, may contribute to the control of tumor progression via downmodulation of E-cadherin protein levels.

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Section: Discussionsupporting

confidence: 52%

The Autophagy Machinery Contributes to E-cadherin Turnover in Breast Cancer

Damiano

Spessotto

Vanin

et al. 2020

Front. Cell Dev. Biol.

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“…Accumulating evidence has demonstrated that SIRT1 is an inducer of EMT and promotes cancer progression (32,33). In the present study, the expression of E-cadherin was increased while that of vimentin was decreased in A549 cells transfected with miR-448 mimics, suggesting that miR-448 reverses EMT by repressing SIRT1 expression.…”

Section: Discussionsupporting

confidence: 54%

miR‑448 promotes progression of non‑small‑cell lung cancer via targeting SIRT1

Qi¹,

Wang

Pang³

2019

Exp Ther Med

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Deregulation of microRNAs (miRs) has been demonstrated to be involved in both the initiation and the development of non-small-cell lung cancer (NSCLC). miR-448 has been identified as a tumor suppressor in several cancer types. The aim of the present study was to explore the role of miR-448 in NSCLC. Tumor tissues and paired normal tissues were obtained from patients with NSCLC. The viability and migration of A549 cells were determined by the Cell Counting kit-8 and wound-healing assays, respectively. Gene and protein levels were detected by reverse transcription-quantitative polymerase chain reaction analysis and western blotting, respectively. The interaction between the 3' untranslated region of sirtuin1 (SIRT1) and miR-448 was predicted by TargetScan and verified by dual luciferase reporter assay. miR-448 levels were revealed to be decreased whereas SIRT1 levels were increased in NSCLC tissues compared with normal tissues. Pearson's correlation analysis demonstrated that there was a negative correlation between miR-448 and SIRT1 mRNA levels. Overexpression of miR-448 led to reduced growth and migration ability of A549 cells. In addition, overexpression of miR-448 decreased SIRT1 mRNA and protein levels, thereby inhibiting epithelial-mesenchymal transition (EMT) and affecting EMT-associated molecules, including vimentin and E-cadherin. Dual luciferase reporter assay confirmed that SIRT1 was a direct target of miR-448. Notably, activation of SIRT1 by resveratrol treatment partially reversed the cell growth inhibition induced by miR-448 mimics. These findings suggested that the progression of NSCLC may be controlled by miR-448, which appears to hold promise as a therapeutic target for patients with NSCLC.

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“…Additionally, Sun et al found that SIRT1 promotes melanocyte proliferation and metastasis by inducing epithelial-mesenchymal transition (EMT) by autophagic degradation of epithelial marker E-cadherin through deacetylation of Beclin 1 (27). Furthermore, SIRT1 inhibition decreased mesenchymal markers Vimentin and N-cadherin, while E-cadherin was increased (27). The aforementioned studies suggest that targeting SIRT1 might be crucial to the regulation of several key targets involved in melanoma progression (Figure 1B).…”

Section: The Sirtuins Sirt1 and Sirt3 And Their Downstream Targets Imentioning

confidence: 94%