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. 2020 Oct;19(20):2644-2652.
doi: 10.1080/15384101.2020.1814044. Epub 2020 Sep 14.

Methionine represses the autophagy of gastric cancer stem cells via promoting the methylation and phosphorylation of RAB37

Lin Xin  1 , Shi-Hao Li  1 , Chuan Liu  1 , Fei Zeng  1 , Jia-Qing Cao  1 , Li-Qiang Zhou  1 , Qi Zhou  1 , Yi-Wu Yuan  1
Affiliations

Methionine represses the autophagy of gastric cancer stem cells via promoting the methylation and phosphorylation of RAB37

Lin Xin et al. Cell Cycle. 2020 Oct.

Abstract

This study focused on the role of methionine (MET) in the autophagy of gastric cancer stem cells (GCSCs) and aims to elaborate its regulatory mechanism. In the present study, the GCSCs were isolated from human gastric cancer cell lines using an anti-CD44 antibody, and then cultured in MET+ homocysteine (HCY)- or MET-HCY+ medium. In MET+HCY-treated GCSCs, autophagy was suppressed, the methylation and phosphorylation of RAB37 were elevated, and miR-200b expression was down-regulated. Lentiviral vector (LV-) carrying methionine-γ lyase (an enzyme that could specifically lyse MET; Metase) promoted autophagy, reduced the methylation and phosphorylation of RAB37, and up-regulated miR-200b expression in MET+HCY--treated GCSCs. Then, we found that miR-200b suppressed the expression of protein kinase C α (PKCα), a protein that could inactivate RAB37 through promoting its phosphorylation. LV-Metase down-regulated RAB37 phosphorylation via miR-200b/PKCα, thus promoting the RAB37-mediated autophagy and suppressing cell viability in MET+HCY-treated GCSCs. Finally, the in vivo study proved that LV-Metase treatment inhibited tumor growth through up-regulating RAB37 expression. In conclusion, MET suppressed RAB37 expression via enhancing its methylation and suppressed RAB37 activity via miR-200b/PKCα axis, thus repressing RAB37-mediated autophagy in GCSCs. The supplementation of Metase lysed MET, thus inducing the autophagy of GCSCs and inhibiting tumor growth.

Keywords: Methionine; RAB37; autophagy; gastric cancer stem cells; methionine-γ lyase.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Autophagy was elevated in gastric cancer stem cells (GCSCs)
Figure 2.
Figure 2.
MET increased the methylation and phosphorylation of RAB37 and suppressed autophagy in GCSCs
Figure 3.
Figure 3.
Metase supplementation reduced the methylation and phosphorylation of RAB37 and promoted autophagy in GCSCs
Figure 4.
Figure 4.
miR-200b negatively regulated PKCα expression in GCSCs
Figure 5.
Figure 5.
miR-200b/PKCα axis was involved in the promoting effect of Metase on autophagy of GCSCs by regulating the phosphorylation level of RAB37
Figure 6.
Figure 6.
Metase suppressed tumor growth by enhancing the expression and activity of RAB37 in vivo.
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