SIRT6 drives epithelial-to-mesenchymal transition and metastasis in non-small cell lung cancer via snail-dependent transrepression of KLF4.

Abstract

BACKGROUND:

Epithelial-to-mesenchymal transition (EMT) contributes to the invasion and metastasis of epithelial tumors. Sirtuin 6 (SIRT6), an NAD-dependent deacetylase, is known to promote metastasis of non-small cell lung cancer (NSCLC).

METHODS:

In this work, we determined the role of SIRT6 in the EMT of NSCLC cells and identified the key EMT-related genes involved in the oncogenic activity of SIRT6.

RESULTS:

We report that depletion of SIRT6 inhibits transforming growth factor-β1 (TGF-β1)-induced EMT in A549 and H1299 NSCLC cells, which is rescued by ectopic expression of SIRT6. Knockdown of SIRT6 leads to a reduction in Snail protein without affecting the mRNA level. Immunoprecipitation experiments demonstrate a physical association between SIRT6 and Snail. SIRT6 deacetylates Snail and prevents its proteasomal degradation. Silencing of Snail blunts SIRT6-induced NSCLC cell migration and invasion, while overexpression of Snail restores the invasion and EMT in SIRT6-depleted NSCLC cells. SIRT6 depletion leads to an upregulation of kruppel-like factor 4 (KLF4) and reduced Snail binding to the promoter of Klf4 in NSCLC cells. Knockdown of KLF4 rescues the invasive capacity in SIRT6-depleted NSCLC cells. Conversely, co-expression of KLF4 impairs SIRT6-induced aggressive behavior. In vivo data further demonstrate that SIRT6-induced NSCLC metastasis is antagonized by overexpression of KLF4.

CONCLUSIONS:

These findings provide mechanistic insights into the pro-metastatic activity of SIRT6 and highlight the role of the SIRT6/Snail/KLF4 axis in regulating EMT and invasion of NSCLC cells.

• Authors: Ziming Li, Jia Huang, Shengping Shen, Zhenping Ding, Qingquan Luo, Zhiwei Chen, Shun Lu
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 37 Issue 1 Pg. 323 (Dec 22 2018) ISSN: 1756-9966 [Electronic] England
• PMID: 30577808 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Transforming Growth Factor beta1
• SIRT6 protein, human
• Sirtuins

Topics

• A549 Cells
• Animals
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology)
• Epithelial-Mesenchymal Transition
• Heterografts
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Lung Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Sirtuins (genetics, metabolism)
• Transfection
• Transforming Growth Factor beta1 (pharmacology)