Histone H3 lysine-trimethylation markers are decreased by recombinant methioninase and increased by methotrexate at concentrations which inhibit methionine-addicted osteosarcoma cell proliferation

Biochemistry and Biophysics Reports

Kazuyuki Hamada¹  Qinghong Han²  Yasunori Tome³  Kotaro Nishida³  Yusuke Aoki⁴  Robert M. Hoffman⁴  Michael Bouvet⁴  Noriyuki Masaki⁴  Jun Yamamoto⁵ 

[1] Corresponding author. Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 07 Uehara, Nishihara, Okinawa, 903-0125, Japan.;Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0125, Japan;Department of Surgery, University of California, San Diego, 9300 Campus Point Drive 7220, La Jolla, CA, 92037-7220, USA;AntiCancer Inc, 7917 Ostrow St, San Diego, CA, 92111, USA;Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0125, Japan;

关键词: Osteosarcoma;    Recombinant methioninase;    Methionine restriction;    Methotrexate;    Methylation;    Histone;   

DOI  :  

来源: DOAJ

【 摘 要 】

Methionine addiction is a fundamental and general hallmark of cancer cells, which require exogenous methionine, despite their ability to synthesize normal amounts of methionine from homocysteine. In contrast, methionine-independent normal cells do not require exogenous methionine in the presence of a methionine precursor. The methionine addiction of cancer cells is due to excess transmethylation reactions. We have previously shown that histone H3 lysine marks are over-methylated in cancer cells and the over-methylation is unstable when the cancer cells are restricted of methionine. In the present study, we show that methionine-addicted osteosarcoma cells are sensitive to both methotrexate (MTX) and recombinant methioninase (rMETase), but they affect histone H3 lysine-methylation in the opposite direction. Concentrations of MTX and rMETase, which inhibit osteosarcoma cells viability to 20%, had opposing effects on the status of histone methylation of H3K9me3 and H3K27me3. rMETase significantly decreased the amount of H3K9me3 and H3K27me3. In contrast, MTX significantly increased the amount of H3K9me and H3K27me3. The results suggest that increase or decrease in these methylated histone lysine marks is associated with proliferation arrest of methionine-addicted osteosarcoma.

【 授权许可】

Unknown