Extent and Instability of Trimethylation of Histone H3 Lysine Increases With Degree of Malignancy and Methionine Addiction

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 12 This article is freely accessible online.

Linkage of methionine addiction, histone lysine hypermethylation, and malignancy

“…The present study along with our recent study (Yamamoto et al, 2020a), suggest that malignant cells require histone H3 lysine hypermethylation to grow in vitro and to form tumors and metastasis in vivo. Our recent results have demonstrated that high malignancy variants of methionine-addicted parental cancer cells, become even more methionine-addicted, form large tumors, and increase the amount of trimethylated histone H3 lysine marks (Yamamoto et al, 2022), further emphasizing the close association of the three phenomena. The present study thus shows that histone H3 pan-overmethylated lysine marks explain, at least in part, the fate of an important set of methyl-groups in cancer cells and why cancer cells are methionine addicted, but not normal cells or methionine-independent revertant cells.…”

“…Methionine addiction is a fundamental and general hallmark of cancer and is known the Hoffman effect (Coalson et al, 1982;Hoffman and Erbe, 1976;Kaiser, 2020;Stern et al, 1983 and is an area of current intense interest (Gao et al, 2019;Wang et al, 2019;Yamamoto et al, 2020aYamamoto et al, , 2021Yamamoto et al, , 2022. Methionine addiction is characterized by a requirement for exogenous methionine for growth by cancer cells even though the methionine-addicted cancer cells synthesize normal or excess amounts of methionine (Coalson et al, 1982;Hoffman and Erbe, 1976;Stern et al, 1983;Wang et al, 2019).…”

“…The Hoffman effect of methionine addiction is analogous to the Warburg effect for glucose overuse by cancer cells (Borrego et al, 2016;Kaiser, 2020). Methionine addiction is tightly linked to other hallmarks of cancer (Borrego et al, 2016;Hoffman et al, 1979;Yamamoto et al, 2020aYamamoto et al, , 2021Yamamoto et al, , 2022 and is thought possibly the very basis of malignancy itself (Hoffman, 2017).…”

“…Although we have long since known methionine is overused for transmethylation reactions in cancer cells (Judde et al, 1989;, we have poorly understood the fate of at least a significant amount of the excess methyl groups that were transferred. Our previous studies have shown that histone H3 lysine marks are overmethylated in cancer cells compared to normal cells (Aoki et al, 2021;Yamamoto et al, 2020aYamamoto et al, , 2021Yamamoto et al, , 2022 and that the histone H3 lysine hypermethylation is unstable during methionine restriction of methionine-addicted cancer cells which arrests their proliferation (Yamamoto et al, 2020a).…”

Long-term Stable Disease in a Rectal-cancer Patient Treated by Methionine Restriction With Oral Recombinant Methioninase and a Low-methionine Diet

“…Methionine addiction is a fundamental and general hallmark of cancer cells (5-7) (21)(22)(23). We previously showed that even though cancer cells can synthesize methionine from homocysteine to a similar or greater extent than normal cells, they require a large amount of exogenous methionine due to excess transmethylation reactions (9)(10)(11)24). Gao et al reported that methionine restriction enhanced the therapeutic response in RAS-driven colorectal cancer and soft-tissue sarcoma in patient-derived xenograft models (PDX) (25), confirming results we found more than 25 years earlier (26)(27)(28).…”