Role of methionine adenosyltransferase genes in hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Detection of HCC can be difficult, as most of the patients who develop this tumor have no symptoms other than those related to their longstanding liver disease. There is an urgent need to understand the molecular mechanisms that are responsible for the development of this disease so that appropriate therapies can be designed. Methionine adenosyltransferase (MAT) is an essential enzyme required for the biosynthesis of S-adenosylmethionine (AdoMet), an important methyl donor in the cell. Alterations in the expression of MAT genes and a decline in AdoMet biosynthesis are known to be associated with liver injury, cirrhosis and HCC. This review focuses on the role of MAT genes in HCC development and the scope for therapeutic strategies using these genes.

Figure 1.

Methionine metabolism in liver. The first step in methionine metabolism is catalyzed by methionine adenosyltransferase (MAT), generating S-adenosylmethionine (AdoMet), which is converted to AdoHcy during transmethylation reactions. AdoHcy hydrolase catalyzes the reversible hydrolysis of AdoHcy to yield homocysteine and adenosine. In the liver, homocysteine can undergo three metabolic pathways (labeled as 1, 2 and 3). First is the transsulfuration pathway, which converts homocysteine to cysteine through a two-step process consisting of two vitamin B₆ dependent enzymes, cystathionine β-synthase (CBS) and γ-cystathionase. Cysteine is further utilized for biosynthesis of GSH. The other two pathways that metabolize homocysteine re-synthesize methionine from homocysteine. One is catalyzed by methionine synthase (MS) and the other is catalyzed by betaine homocysteine methyltransferase (BHMT). Remethylation of homocysteine via MS requires 5-methyltetrahydrofolate (5-MTHF), which is derived from 5,10-methylenetetrahydrofolate (5,10-MTHF) in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted to tetrahydrofolate (THF) as it donates its methyl group and THF is converted to 5,10-MTHF to complete the folate cycle. AdoMet is also utilized in the synthesis of polyamines, thereby generating methylthioadenosine (MTA) [9].

Figure 2.

Mechanisms of HCC development in the MAT1A knockout mouse model. Several mechanisms have been recently elucidated that may promote the development of HCC in the MAT1A KO mice. These include: (1) Development of CD133⁺/CD49f⁺ liver cancer stem cells that have tumorigenic potential in nude mice, exhibit increased expression of certain oncogenes such as K-ras and survivin and are resistant to apoptosis mediated by TGF-β; (2) increased oxidative stress associated with a decrease in APEX1 protein stability and enhanced genomic instability (GI) leading to malignant transformation; (3) reduced DUSP1 expression, which allows ERK activity to go unchecked leading to phosphorylation of DUSP1 at Ser296 that further promote DUSP1 proteasomal degradation and uncontrolled ERK activation; (4) enhanced LKB1 activity leading to AMPK activation that further causes translocation of HuR protein from nucleus to cytoplasm. This leads to stabilization of cyclins thereby promoting growth and malignant transformation.