Journal
ONCOGENE
Volume 33, Issue 12, Pages 1527-1537Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.104
Keywords
HDAC inhibitor; gastric cancer; RNH1; ROS
Funding
- NMRC TCR grant [TCR/001/2007]
- Duke-NUS core grant
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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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