Oncotarget

Research Papers:

Metformin alters H2A.Z dynamics and regulates androgen dependent prostate cancer progression

Monica Tyagi, Manjinder S. Cheema, Deanna Dryhurst, Christopher H. Eskiw and Juan Ausió _

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Oncotarget. 2018; 9:37054-37068. https://doi.org/10.18632/oncotarget.26457

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Abstract

Monica Tyagi1, Manjinder S. Cheema1, Deanna Dryhurst2, Christopher H. Eskiw3 and Juan Ausió1

1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada

2ImmunoPrecise Antibodies Ltd., Victoria, BC, Canada

3Department of Food and Bioproduct Sciences, University of Saskatchewan, Saskatoon, SK, Canada

Correspondence to:

Juan Ausió, email: [email protected]

Keywords: metformin; prostate cancer; H2AZ; androgen receptor

Received: April 19, 2018     Accepted: November 05, 2018     Published: December 11, 2018

ABSTRACT

Epigenetic mechanisms involved in prostate cancer include hypermethylation of tumor suppressor genes, general hypomethylation of the genome, and alterations in histone posttranslational modifications (PTMs). In addition, over expression of the histone variant H2A.Z as well as deregulated expression of Polycomb group proteins including EZH2 have been well-documented. Recent evidence supports a role for metformin in prostate cancer (PCa) treatment. However, the mechanism of action of metformin in PCa is poorly understood. We provide data showing that metformin epigenetically targets PCa by altering the levels and gene binding dynamics of histone variant H2A.Z. Moreover, we show that the increase in H2A.Z upon metformin treatment occurs preferentially due to H2A.Z.1 isoform. Chromatin immunoprecipitation (ChIP)-RT PCR analysis indicates that metformin treatment results in an increased H2A.Z occupancy on the androgen receptor (AR) and AR-regulated genes that is more prominent in the androgen dependent AR positive LNCaP cells. Repression of H2A.Z.1 gene by siRNA–mediated knock down identified this H2A.Z isoform to be responsible. Based on preliminary data with an EZH2-specific inhibitor, we suggest that the effects of metformin on the early stages of PCa may involve both EZH2 and H2A.Z through the alteration of different molecular pathways.


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