PT  - JOURNAL ARTICLE
AU  - Jun Yamamoto
AU  - Sachiko Inubushi
AU  - Qinghong Han
AU  - Yoshihiko Tashiro
AU  - Yu Sun
AU  - Norihiko Sugisawa
AU  - Kazuyuki Hamada
AU  - Hiroto Nishino
AU  - Yusuke Aoki
AU  - Kentaro Miyake
AU  - Ryusei Matsuyama
AU  - Michael Bouvet
AU  - Itaru Endo
AU  - Robert M. Hoffman
TI  - Cancer-specific overmethylation of histone H3 lysines is linked with methionine addiction and malignancy
AID  - 10.1101/2020.12.04.412437
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.12.04.412437
4099  - http://biorxiv.org/content/early/2021/03/13/2020.12.04.412437.short
4100  - http://biorxiv.org/content/early/2021/03/13/2020.12.04.412437.full
AB  - Methionine addiction is a fundamental and general hallmark of cancer and is an area of current intense interest. Methionine addiction results from the overuse of methionine by cancer cells for excess transmethylation reactions. In order to identify excess transmethylation reactions in cancer and further understand the basis of methionine addiction, we compared the histone H3 lysine methylation status between methionine-addicted cancer cells, normal cells and rare revertants of methionine-addicted cancer cells which regained methionine independence and lost malignancy. The levels of H3K4me3, H3K9me3 and H3K36me3 were strongly elevated in methionine-addicted cancer cells in vitro compared to methionine-independent revertants isolated from the cancer cells. Tumorigenicity and experimental metastatic potential in nude mice were highly reduced in the methionine-independent revertants compared to the parental cells. Our previous studies showed that methionine restriction (MR) selectively arrests methionine-addicted cancer cells due to loss of histone H3 lysine methylation which was stable in normal cells under MR. Our previous and present results suggest that overmethylation of histone H3 lysine is linked with methionine addiction of cancer, required for the growth of cancer cells in vitro and in vivo, and necessary for malignancy as the histone lysine overmethylation disappears when the methionine-addicted cells revert to methionine independence and reduced malignancy. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and presents great potential as a pan-cancer therapeutic target.Competing Interest StatementThe authors have declared no competing interest.