Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells

Yamamoto, Jun; Han, Qinghong; Inubushi, Sachiko; Sugisawa, Norihiko; Hamada, Kazuyuki; Nishino, Hiroto; Miyake, Kentaro; Kumamoto, Takafumi; Matsuyama, Ryusei; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M.

doi:10.1016/j.bbrc.2020.09.108

Cited by 49 publications

(81 citation statements)

References 21 publications

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“…These results indicated that malignancy was decreased in methionine-independent revertants compared to parental methionine-addicted cancer cells, due to the decrease in histone H3 lysine methylation. The results of the present study and our previous study (14) indicate that overmethylation of lysines in histone H3 is necessary for both methionine addiction of cancer cells and their malignancy.…”

Section: Resultssupporting

confidence: 80%

“…Mentch et al showed that tri-methyl histone H3 was unstable in cancer cells under MR but did not examine the stability of tri-methyl histone H3 in normal cells under MR (21). Our recent previous study also demonstrated that histone H3K4me3 and H3K9me3 were unstable in cancer cells under MR; and we showed for the first time H3K4me3 and H3K9me3 were stable in normal cells under MR (14), which explains why cancer cells arrest under MR and normal cells do not. And most importantly, the present study shows that pan-histone H3 lysine, H3K4me3 and H3K9me3 are not over methylated in normal cells or in methionine-independent revertants that have decreased malignancy and lost methionine addiction, and can proliferate under MR.…”

Section: Discussionsupporting

confidence: 62%

“…1A) and decreased the levels of H3K4me3 and H3K9me3 in cancer cells while arresting their proliferation (Fig. 1B) (14). In contrast, MR did not affect the levels of histone H3 methylation in normal fibroblasts and did not arrest their proliferation (14).…”

Section: Resultsmentioning

confidence: 99%

“…1B) (14). In contrast, MR did not affect the levels of histone H3 methylation in normal fibroblasts and did not arrest their proliferation (14). These results demonstrate that MR selectively suppressed overmethylation of histone H3 lysine in cancer cells while selectively arresting their proliferation, both in contrast to normal cells…”

Section: Resultsmentioning

confidence: 99%

“…Extraction of histone from cells and tumors and immunoblotting were performed as described (14). Anti-H3K4me3 antibody (1:1,000, #9751, Cell Signaling Technology, Danvers, MA, USA); anti-H3K9me3 antibody (1:1,000, #13969, Cell Signaling Technology); or anti-pan methyl lysine antibody (1:2,000, ab7315, Abcam, Cambridge, UK) for detection of pan methyl lysine of histone H3 were used as the primary antibody.…”

Section: Methodsmentioning

confidence: 99%

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The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

Yamamoto

Inubushi²,

Han

et al. 2020

Preprint

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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 StatementAll 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.

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Section: Resultssupporting

confidence: 80%

Section: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

Yamamoto

Inubushi²,

Han

et al. 2020

Preprint

Self Cite

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Amino acid metabolism as a therapeutic target in cancer: a review

2021

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Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.

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Methionine as a double-edged sword in health and disease: Current perspective and future challenges

Navik

Sheth

Khurana

et al. 2021

Ageing Research Reviews

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Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells

Cited by 49 publications

References 21 publications

The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

The linkage of methionine addiction, overmethylation of histone H3 lysines and malignancy demonstrated when cancer cells revert to methionine-independence

Amino acid metabolism as a therapeutic target in cancer: a review

Methionine as a double-edged sword in health and disease: Current perspective and future challenges

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