Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer

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Abstract

Chromosomal abnormalities are good guideposts when hunting for cancer-related genes. We analyzed copy number alterations of 163 primary gastric cancers using array-based comparative genomic hybridization and simultaneously performed a genome-wide integrated analysis of copy number and gene expression using microarray data for 58 tumors. We showed that chromosome 6p21 amplification frequently occurred secondary to ERBB2 amplification, was associated with poorer prognosis and caused overexpression of half of the genes mapped. A comprehensive small interfering RNA knockdown of 58 genes overexpressed in tumors identified 32 genes that reduced gastric cancer cell growth. Enforced expression of 16 of these genes promoted cell growth in vitro, and six genes showing more than two-fold activity conferred tumor-forming ability in vivo. Among these six candidates, GLO1, encoding a detoxifying enzyme glyoxalase I (GLO1), exhibited the strongest tumor-forming activity. Coexpression of other genes with GLO1 enhanced growth-stimulating activity. A GLO1 inhibitor, S-p-bromobenzyl glutathione cyclopentyl diester, inhibited the growth of two-thirds of 24 gastric cancer cell lines examined. The efficacy was found to be associated with the mRNA expression ratio of GLO1 to GLO2, encoding glyoxalase II (GLO2), another constituent of the glyoxalase system. GLO1 downregulation affected cell growth through inactivating central carbon metabolism and reduced the transcriptional activities of nuclear factor kappa B and activator protein-1. Our study demonstrates that GLO1 is a novel metabolic oncogene of the 6p21 amplicon, which promotes tumor growth and aberrant transcriptional signals via regulating cellular metabolic activities for energy production and could be a potential therapeutic target in gastric cancer.

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Acknowledgements

We thank Setsuo Hirohashi for generous support and encouragement; Yukihiro Nakanishi for advice on histological classification of gastric tumors; Tokuki Sakiyama and Go Maeno for helping with the analysis of the aCGH data; Jun Yasuda for advice on the RNA interference techniques; Yu Nakamura, Michiyo Fukushima, Satomi Uryu and Yasuko Kuwabara for providing considerable contributions to the sample preparation of BAC DNA and patients’ DNA and array hybridization; and Sayaka Kadoguchi and Kenjiro Kami for advice on metabolome analysis. This research was supported in part by a Grant-in-Aid for the Comprehensive 10-Year-Strategy for Cancer Control and from the Ministry of Health, Labor and Welfare, Japan, a grant from the New Energy and Industrial Technology Development Organization (NEDO), Japan and a grant from the National Institute of Biomedical Innovation (NiBio), Japan. MM and NK were recipients of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research in Japan.

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Correspondence to T Shibata.

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Hosoda, F., Arai, Y., Okada, N. et al. Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer. Oncogene 34, 1196–1206 (2015) doi:10.1038/onc.2014.57

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