A SUMOylation-dependent pathway regulates SIRT1 transcription and lung cancer metastasis.

Abstract

BACKGROUND:

Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in lung cancer metastasis. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. The role of SIRT1 in lung cancer EMT is largely undefined.

METHODS:

The effect of SIRT1 on migration of lung cancer cells was evaluated by wound healing assay in vitro and metastasis assay in nude mice in vivo. Protein expression in human lung cancers and cultured lung cancer cells was assessed by western blotting and immunohistochemistry. Interaction between protein and DNA was measured by chromatin immunoprecipitation assay. SIRT1 promoter activity was determined by reporter assay.

RESULTS:

SIRT1 activation antagonized migration of lung cancer cells by suppressing EMT in vitro. Activation of SIRT1 by resveratrol also statistically significantly hampered (by 68.33%; P < .001, two-sided test) lung cancer cell metastasis in vivo. Hypoxia repressed SIRT1 transcription through promoting the competition between Sp1 and HIC1 on the SIRT1 proximal promoter in a SUMOylation-dependent manner. Disruption of SUMOylation by targeting either Ubc9 or PIASy restored SIRT1 expression in and favored an epithelial-like phenotype of cancer cells, thereby preventing metastasis. Decreased SIRT1 combined with elevated PIASy expression was implicated in more-invasive types of lung cancers in humans.

CONCLUSIONS:

We have identified a novel pathway that links SIRT1 down-regulation to hypoxia-induced EMT in lung cancer cells and may shed light on the development of novel antitumor therapeutics.

• Authors: Lina Sun, He Li, Junliang Chen, Vanessa Dehennaut, Yuhao Zhao, Yuyu Yang, Yasumasa Iwasaki, Brigitte Kahn-Perles, Dominique Leprince, Qi Chen, Aiguo Shen, Yong Xu
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 105 Issue 12 Pg. 887-98 (Jun 19 2013) ISSN: 1460-2105 [Electronic] United States
• PMID: 23704280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PIAS4 protein, human
• Poly-ADP-Ribose Binding Proteins
• Protein Inhibitors of Activated STAT
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Animals
• Blotting, Western
• Cell Hypoxia
• Down-Regulation
• Epithelial-Mesenchymal Transition
• Humans
• Immunoprecipitation
• Lung Neoplasms (genetics, pathology)
• Mice
• Mice, Nude
• Neoplasm Staging
• Poly-ADP-Ribose Binding Proteins
• Protein Inhibitors of Activated STAT (metabolism)
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Sirtuin 1 (genetics, metabolism)
• Sumoylation
• Transcription, Genetic
• Tumor Cells, Cultured
• Up-Regulation