RT Journal Article
SR Electronic
T1 Cancer-specific overmethylation of histone H3 lysines is necessary for methionine addiction and malignancy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.04.412437
DO 10.1101/2020.12.04.412437
A1 Jun Yamamoto
A1 Sachiko Inubushi
A1 Qinghong Han
A1 Yoshihiko Tashiro
A1 Yu Sun
A1 Norihiko Sugisawa
A1 Kazuyuki Hamada
A1 Hiroto Nishino
A1 Yusuke Aoki
A1 Kentaro Miyake
A1 Ryusei Matsuyama
A1 Michael Bouvet
A1 Itaru Endo
A1 Robert M. Hoffman
YR 2020
UL http://biorxiv.org/content/early/2020/12/06/2020.12.04.412437.abstract
AB Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction results from the overuse of methionine by cancer cells for excess transmethylation reactions. In order to identify excess transmethylation reactions in cancer, we compared the histone H3 lysine methylation status between methionine-addicted cancer cells, normal cells and revertants of methionine-addicted cancer cells which regained methionine independence and lost malignancy. The levels of H3K4me3, H3K9me3 and pan-methyl lysine of histone H3 were elevated in methionine-addicted cancer cells in vitro compared to methionine-independent revertants isolated from the cancer cells and to normal cells. Tumorigenicity in nude mice was highly reduced in the methionine-independent revertants compared to the parental cells. The methionine-independent revertants no longer overmethylated pan-methyl lysine of H3, H3K4me3 and H3K9me3. 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 necessary for methionine addiction of cancer, required for the growth of cancer cells in vitro and in vivo, and necessary for malignancy. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and presents great potential as a pan-cancer therapeutic target.Signiificance Statement All cancer cell types are methionine-addicted. Methionine addiction is due to the overuse of methionine by cancer cells for excess transmethylation reactions. In the present study, we showed that the level of histone H3 lysine methylation was elevated in methionine-addicted cancer cells compared to normal fibroblasts and methionine-independent revertants with reduced malignancy that were derived from the methionine-addicted cancer cells. These results suggest that overmethylation of histone H3 lysine is necessary for methionine addiction of cancer and malignancy itself. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and has been shown to be a universal therapeutic target in numerous pre-clinical studies of all major cancer types and has great clinical potential.Competing Interest StatementThe authors have declared no competing interest.