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  • Original Article
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SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis

Oncogene volume 31, pages 4619–4629 (2012)Cite this article

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Abstract

The epithelial-to-mesenchymal transition (EMT) is a crucial program for the invasion and metastasis of epithelial tumors that involves loss of cell–cell adhesion and increased cell mobility; however, mechanisms underlying this transition are not fully elucidated. Here, we propose a novel mechanism through which the nicotinamide adenine dinucleotide-dependent histone deacetylase SIRT1 regulates EMT in prostate cancer cells through cooperation with the EMT inducing transcription factor ZEB1. We found that forced expression of SIRT1 in non-transformed PZ-HPV-7 prostate epithelial cells disrupts the epithelial morphology concomitant with decreased expression of the epithelial marker, E-cadherin, and increased expression of mesenchymal markers. In contrast, silencing SIRT1 in metastatic prostate tumor cells restores cell–cell adhesion and induces a shift toward an epithelial morphology concomitant with increased expression of E-cadherin and decreased expression of mesenchymal markers. We also found that SIRT1 has a physiologically relevant role in endogenous EMT induced by EGF signaling in prostate cancer cells. We propose that the regulation of EMT by SIRT1 involves modulation of, and cooperation with, the EMT inducing transcription factor ZEB1. Specifically, we show that SIRT1 silencing reduces expression of ZEB1 and that SIRT1 is recruited to the E-cadherin proximal promoter by ZEB1 to deacetylate histone H3 and to reduce binding of RNA polymerase II, ultimately suppressing E-cadherin transcription. We thus identify a necessary role for ZEB1 in SIRT1-mediated EMT. Finally, we show that reduction of SIRT1 decreases prostate cancer cell migration in vitro and metastasis in vivo in immunodeficient mice, which is largely independent of any general effects of SIRT1 on prostate cancer growth and survival. We therefore identify SIRT1 as a positive regulator of EMT and metastatic growth of prostate cancer cells and our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse EMT and to prevent prostate cancer progression.

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Acknowledgements

We thank Dr F Picard (Laval University, Canada), Dr Michael Korn (USCF, CA), Dr M Ott (UCSF, CA) for providing plasmid constructs. We greatly thank the technical support in tumor cell s.c. injection from Dr Zhijun Luo (Boston University School of Medicine). We thank Lora Forman for the technical assistant (Boston University) and Christine Chiao (Boston University) for the proofreading of this manuscript. This work was supported by grants from the National Cancer Institute (1R21CA141036) (YD), the Clinical and Translational Science Institute award of NIH (UL1RR025771) (YD), the National Cancer Institute (CA101992) (DVF), the Karin Grunebaum Cancer Research Foundation (YD and DVF), the American Cancer Society (IRG-72-001-27-IRG) (YD), and the Department of Medicine Pilot Project Grant Award (YD).

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  1. V Byles and L Zhu: These authors contributed equally to this study.

Authors and Affiliations

  1. Cancer Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    V Byles, L Zhu, J D Lovaas, L K Chmilewski, J Wang, D V Faller & Y Dai

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  1. V Byles
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Correspondence to Y Dai.

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Byles, V., Zhu, L., Lovaas, J. et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene 31, 4619–4629 (2012). https://doi.org/10.1038/onc.2011.612

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