A novel mechanism of the M1‐M2 methionine adenosyltransferase switch‐mediated hepatocellular carcinoma metastasis

Abstract

Hepatocellular carcinoma (HCC) manifests as a highly metastatic cancer with extremely poor prognosis. However, mechanisms underlying metastasis of HCC are not fully understood. Here, we showed that switching gene expression from MAT1A to MAT2A (M1-M2 switch) promoted cancer invasion and metastasis. Reversion of the M1-M2 switch repressed, whereas enhancing the M1-M2 switch promoted the ability of HCC cells to metastasize. Moreover, we provided clinical data showing that tipping the balance between MAT1A and MAT2A expression correlated with increased metastasis and inferior recurrence-free survival in HCC patients. Molecular pathways analysis showed that downregulation of MAT1A, which augmented osteopontin (OPN) expression through decreasing methylation of the OPN promoter, and MAT2A upregulation, which induced integrin β3 (ITGB3) expression by binding to ITGB3 promoter, collaboratively triggered ERK signaling and thereby promoted metastasis. Thus, the simultaneous downregulation of MAT1A and upregulation of MAT2A are necessary and sufficient for HCC metastasis in the process of M1-M2 switch. Our findings provide novel mechanistic insights into cancer metastasis. Inhibition and prevention of the M1-M2 switch would offer a novel therapeutic option for treatment of HCC.

Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA

“…1j ). In agreement with previous findings, 6 , 22 – 24 we also found that the survival period of patients with different cancers displaying high MAT2A expression level became significantly shorter by analyzing overall survival (Supplementary Fig. S1h ).…”

Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice

“…One study showed that enhancing the M1-M2 switch promoted the ability of these cancer cells to metastasize, and this phenomenon was correlated with human data where a balance in favor of M2 (M1 < M2) correlated with increased metastasis and high rate of recurrence in HCC patients. Mechanistically this work highlighted that MAT1A was essential for methylating the promoters of certain genes such as osteopontin (OPN), and by repressing MAT1A expression such genes were freed from methylation-dependent repression and corroborated with other MAT1A activated genes to promote metastasis-driving pathways such as extracellular-signal-regulated kinase (ERK) signaling [19]. Our study however, finds the expression to be tipped in favor of M1 in the bladder, and the downstream outcomes of M1 overexpression may have broader implications including increased survivability in the presence of chemotherapy.…”

Integrins in human hepatocellular carcinoma tumorigenesis and therapy

“…Besides, Li et al [75] showed that ZKSCAN3, a zinc-finger transcription factor, enhances integrin β4 expression by directly binding to the integrin β4 promoter. It has been reported that methionine adenosyltransferases 2A (MAT2A) upregulates integrin β3 expression by directly binding to integrin β3 promoter, which promotes HCC metastasis [90] . Altered histone modifications are also critical epigenetic regulations in gene transcription.…”