Linkage of methionine addiction, histone lysine hypermethylation, and malignancy
Jun Yamamoto,
Sachiko Inubushi,
Qinghong Han,
Yoshihiko Tashiro,
Norihiko Sugisawa,
Kazuyuki Hamada,
Yusuke Aoki,
Kentaro Miyake,
Ryusei Matsuyama,
Michael Bouvet,
Steven G. Clarke,
Itaru Endo,
Robert M. Hoffman
Affiliations
Jun Yamamoto
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Corresponding author
Sachiko Inubushi
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA
Qinghong Han
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA
Yoshihiko Tashiro
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA
Norihiko Sugisawa
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA
Kazuyuki Hamada
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA
Yusuke Aoki
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA
Kentaro Miyake
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Ryusei Matsuyama
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Michael Bouvet
Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA
Steven G. Clarke
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569, USA
Itaru Endo
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Corresponding author
Robert M. Hoffman
AntiCancer Inc, 7917 Ostrow St, San Diego, CA 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA 92037-7220, USA; Corresponding author
Summary: Methionine addiction, found in all types of cancer investigated, is because of the overuse of methionine by cancer cells for excess transmethylation reactions. In the present study, we compared the histone H3 lysine-methylation status and degree of malignancy between methionine-addicted cancer cells and their isogenic methionine-independent revertants, selected by their growth in low concentration of methionine. The methionine-independent revertans can grow on low levels of methionine or independently of exogenous methionine using methionine precursors, as do normal cells. In the methionine-independent revertants, the excess levels of trimethylated histone H3 lysine marks found in the methionine-addicted parental cancer cells were reduced or lost, and their tumorigenicity and experimental metastatic potential in nude mice were also highly reduced. Methionine addiction of cancer is linked with malignancy and hypermethylation of histone H3 lysines. The results of the present study thus provide a unique framework to further understand a fundamental basis of malignancy.
