Jun Yamamoto1,2,3, Yusuke Aoki4,2, Sachiko Inubushi4,2, Qinghong Han4, Kazuyuki Hamada4,2, Yoshihiko Tashiro4,2, Kentaro Miyake3, Ryusei Matsuyama3, Michael Bouvet2, Steven G Clarke5, Itaru Endo6, Robert M Hoffman7,2. 1. AntiCancer Inc., San Diego, CA, U.S.A.; all@anticancer.com. 2. Department of Surgery, University of California, San Diego, La Jolla, CA, U.S.A. 3. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 4. AntiCancer Inc., San Diego, CA, U.S.A. 5. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, U.S.A. 6. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan; endoit@yokohama-cu.ac.jp. 7. AntiCancer Inc., San Diego, CA, U.S.A.; jun.ymmt.1014@gmail.com.
Abstract
BACKGROUND/AIM: Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Methionine addiction is due to excessive use of and dependence on methionine by cancer cells. In the present report, we correlated the extent of methionine addiction and degree of malignancy with the amount and stability of methylated histone H3 lysine marks. MATERIALS AND METHODS: We established low- and high-malignancy variants from a parental human pancreatic-cancer cell line and compared their sensitivity to methionine restriction and histone H3 lysine methylation status. RESULTS: A low-malignancy, low-methionine-addiction revertant of the parental pancreatic-cancer cell line had less methylated H3K9me3 and was less sensitive to methionine restriction effected by recombinant methioninase (rMETase) than the parental cell line. A high-malignancy variant of the pancreatic cancer cell line had increased methylated H3K9me3 and was more sensitive to methionine restriction by rMETase with regard to inhibition of proliferation and to instability of histone H3 lysine methylation than the parental cell line. Orthotopic malignancy in nude mice was reduced in the low-methionine-addiction revertant and greater in the high-malignancy variant than in the parental cell line. CONCLUSION: The present study indicates that the degree of malignancy is linked to the extent of methionine addiction and the level and instability of trimethylation of histone H3, suggesting these phenomena are linked as a fundamental basis of oncogenic transformation.
BACKGROUND/AIM: Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Methionine addiction is due to excessive use of and dependence on methionine by cancer cells. In the present report, we correlated the extent of methionine addiction and degree of malignancy with the amount and stability of methylated histone H3 lysine marks. MATERIALS AND METHODS: We established low- and high-malignancy variants from a parental human pancreatic-cancer cell line and compared their sensitivity to methionine restriction and histone H3 lysine methylation status. RESULTS: A low-malignancy, low-methionine-addiction revertant of the parental pancreatic-cancer cell line had less methylated H3K9me3 and was less sensitive to methionine restriction effected by recombinant methioninase (rMETase) than the parental cell line. A high-malignancy variant of the pancreatic cancer cell line had increased methylated H3K9me3 and was more sensitive to methionine restriction by rMETase with regard to inhibition of proliferation and to instability of histone H3 lysine methylation than the parental cell line. Orthotopic malignancy in nude mice was reduced in the low-methionine-addiction revertant and greater in the high-malignancy variant than in the parental cell line. CONCLUSION: The present study indicates that the degree of malignancy is linked to the extent of methionine addiction and the level and instability of trimethylation of histone H3, suggesting these phenomena are linked as a fundamental basis of oncogenic transformation.
Authors: Y Tan; M Xu; X Tan; X Tan; X Wang; Y Saikawa; T Nagahama; X Sun; M Lenz; R M Hoffman Journal: Protein Expr Purif Date: 1997-03 Impact factor: 1.650