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Sphingosine Kinase 1 Is Required for Mesothelioma Cell Proliferation: Role of Histone Acetylation

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posted on 19.11.2013, 00:00 by Satish Kalari, Nagabhushan Moolky, Srikanth Pendyala, Evgeny V. Berdyshev, Cleo Rolle, Rajani Kanteti, Archana Kanteti, Wenli Ma, Donghong He, Aliya N. Husain, Hedy L. Kindler, Prasad Kanteti, Ravi Salgia, Viswanathan Natarajan
Background: Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics. Methodology/Principal Findings: In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK12/2 null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts. Conclusions/Significance: The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.

Funding

This work was supported by the National Institutes of Health (NIH), start up funds, and the University of Illinois at Chicago (UIC).

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Publisher Statement

The original version is available through Public Library of Science at DOI: 10.1371/journal.pone.0045330. © 2012 Kalari, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Kalari S, Moolky N, Pendyala S, Berdyshev EV, Rolle C, et al. (2012) Sphingosine Kinase 1 Is Required for Mesothelioma Cell Proliferation: Role of Histone Acetylation. PLoS ONE 7(9): e45330. doi:10.1371/journal.pone.0045330

Publisher

Public Library of Science

Language

en_US

issn

1932-6203

Issue date

01/09/2012

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