Resveratrol regulates PTEN/Akt pathway through inhibition of MTA1/HDAC unit of the NuRD complex in prostate cancer.

Abstract

Metastasis associated protein 1 (MTA1) is a component of the nucleosome remodeling and deacetylating (NuRD) complex which mediates gene silencing and is overexpressed in several cancers. We reported earlier that resveratrol, a dietary stilbene found in grapes, can down-regulate MTA1. In the present study, we show that PTEN is inactivated by MTA1 in prostate cancer cells. Further, we show that resveratrol promotes acetylation and reactivation of PTEN via inhibition of the MTA1/HDAC complex, resulting in inhibition of the Akt pathway. In addition, we show that MTA1 knockdown is sufficient to augment acetylation of PTEN indicating a crucial role of MTA1 itself in the regulation of PTEN acetylation contributing to its lipid phosphatase activity. Acetylated PTEN preferentially accumulates in the nucleus where it binds to MTA1. We also show that MTA1 interacts exclusively with PTEN acetylated on Lys¹²⁵ and Lys¹²⁸, resulting in diminished p-Akt levels. Finally, using orthotopic prostate cancer xenografts, we demonstrate that both resveratrol treatment and MTA1 knockdown enhance PTEN levels leading to a decreased p-Akt expression and proliferation index. Taken together, our results indicate that MTA1/HDAC unit is a negative regulator of PTEN which facilitates survival pathways and progression of prostate cancer and that resveratrol can reverse this process through its MTA1 inhibitory function.

• Authors: Swati Dhar, Avinash Kumar, Kun Li, Guri Tzivion, Anait S Levenson
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1853 Issue 2 Pg. 265-75 (Feb 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25447541 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Histone Deacetylase Inhibitors
• Mta1 protein, human
• Nucleosomes
• Repressor Proteins
• Stilbenes
• Trans-Activators
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human
• Histone Deacetylases
• Mi-2 Nucleosome Remodeling and Deacetylase Complex
• Resveratrol

Topics

• Acetylation (drug effects)
• Animals
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Down-Regulation (drug effects)
• Enzyme Activation (drug effects)
• Gene Knockdown Techniques
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Humans
• Immunoprecipitation
• Male
• Mi-2 Nucleosome Remodeling and Deacetylase Complex (metabolism)
• Mice, Nude
• Models, Biological
• Nucleosomes (drug effects, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Prostatic Neoplasms (enzymology, pathology)
• Protein Binding (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Repressor Proteins (antagonists & inhibitors, metabolism)
• Resveratrol
• Signal Transduction (drug effects)
• Stilbenes (pharmacology)
• Trans-Activators
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays