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RNH1 regulation of reactive oxygen species contributes to histone deacetylase inhibitor resistance in gastric cancer cells

Oncogene volume 33, pages 1527–1537 (2014)Cite this article

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Abstract

Histone deacetylase inhibitors (HDACis) are a promising class of anticancer epigenetic drugs, however, molecular factors influencing the responses of individual tumors to HDACi therapies remain obscure. Here, we sought to identify genes associated with HDACi resistance in gastric cancer. Treating a panel of 17 gastric cancer cell lines with multiple HDACi compounds (trichostatin A, SAHA and MS275), we identified two distinct classes of lines exhibiting either HDACi sensitivity or resistance. Genomic comparisons between the sensitive and resistant classes using two independent microarray platforms identified RNH1, encoding a ribonuclease inhibitor, as a gene highly expressed in HDACi-resistant lines. Using genetic knockdown and overexpression assays, we show that RNH1 is both necessary and sufficient to induce HDACi resistance, and that RNH1 is likely to mediate this resistance through the dampening of HDACi-induced reactive oxygen species (ROS) in cancer cells. The discovery of RNH1 as a regulator of HDACi resistance in gastric cancer highlights a functional role for ROS induction in the cellular effects of this important drug class.

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Acknowledgements

We thank that Dr Shang Li’s lab for the gift of Hela, MCF7, HEPG2 and HCT116 cell lines. This work was funded by NMRC TCR grant TCR/001/2007 and a Duke-NUS core grant.

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Authors and Affiliations

  1. Cancer and Stem Cell and Biology, Duke-NUS Graduate Medical School, Singapore

    Y Zhu, K Das & P Tan

  2. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Y Zhu

  3. Cellular and Molecular Research, National Cancer Centre, Singapore

    J Wu, M H Lee & P Tan

  4. Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    P Tan

  5. Genome Institute of Singapore, Singapore

    P Tan

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Correspondence to P Tan.

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Zhu, Y., Das, K., Wu, J. et al. RNH1 regulation of reactive oxygen species contributes to histone deacetylase inhibitor resistance in gastric cancer cells. Oncogene 33, 1527–1537 (2014). https://doi.org/10.1038/onc.2013.104

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