title: RNH1 regulation of reactive oxygen species contributes to histone deacetylase inhibitor resistance in gastric cancer cells.
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.
authors.affiliation: 1] Cancer and Stem Cell and Biology, Duke-NUS Graduate Medical School, Singapore [2] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Cancer and Stem Cell and Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.affiliation: Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: M H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: 1] Cancer and Stem Cell and Biology, Duke-NUS Graduate Medical School, Singapore [2] Cellular and Molecular Research, National Cancer Centre, Singapore [3] Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [4] Genome Institute of Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Tan
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: D002352:Carrier Proteins; D056572:Histone Deacetylase Inhibitors; C501467:RNH1 protein, human; D017382:Reactive Oxygen Species; D006655:Histone Deacetylases