Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver

Abstract

Carcinogenesis is a multi-step and multifactorial process. It includes genetic, epigenetic, nutritional and environmental factors, which are closely interconnected. Human hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. Imbalance in the S-adenosylmethionine (SAM) concentration, the main methyl group donor, strongly influences the development of HCC. Key enzymes of carbon metabolism are greatly reduced in patients with cirrhosis and HCC. These alterations play a role in genetic instability and epigenetic modifications (DNA methylation, and histone modifications), however, the molecular underlying mechanisms are still poorly understood. We aimed to investigate betaine homocysteine methyltransferase (BHMT) expression in HepG2 cells and human hepatocarcinoma tissues. Tumor and surrounding healthy tissue were compared. HepG2 cells and tumor samples showed a strong decrease in BHMT transcripts resulting from the transcription of a splicing variant that contained a frameshift mutation generating a premature termination codon and gene loss of function. This splicing variant, not detected in normal adult and fetal liver, cannot be explained by any mechanism involving the known splicing consensus sequences. BHMT activity was abolished in HepG2 cells and protein expression was detected neither in HepG2 cells nor in five of the six tumor samples investigated. Further investigation is needed to elucidate whether this abnormal BHMT transcription is part of cause or consequence of liver carcinogenesis.

Serum choline is associated with hepatocellular carcinoma survival: a prospective cohort study

“…As a methyl donor, betaine participates in the re-methylation of homocysteine to methionine via the enzyme betaine homocysteine methyltransferase (BHMT) 27 . However, this key enzyme is greatly reduced in HCC patients 29 , and downregulation of BHMT in HCC associates with poor prognosis 30 . Besides, after treating the Hepa 1-6 (derived cells from a mouse HCC model) and E47/C34 cell lines (clones of the HepG2 cell line) with exogenous S-adenosylmethionine (SAM) and betaine, results showed that SAM decreased the number of Hepa 1-6 and E47/C34 cells, and increased the number of dead cells in vitro, while betaine had no significant effect either on the number of surviving cells or dead cells 31 .…”

Serum choline is associated with hepatocellular carcinoma survival: a prospective cohort study

“…As a methyl donor, betaine participates in the re-methylation of homocysteine to methionine via the enzyme betaine homocysteine methyltransferase (BHMT) [26]. However, this key enzyme is greatly reduced in HCC patients [28], and downregulation of BHMT in HCC associates with poor prognosis [29]. Besides, after treating the Hepa 1-6 (derived cells from a mouse HCC model) and E47/C34 cell lines (clones of the HepG2 cell line) with exogenous S-adenosylmethionine (SAM) and betaine, results showed that SAM decreased the number of Hepa 1-6 and E47/C34 cells, and increased the number of dead cells in vitro, while betaine had no significant effect either on the number of surviving cells or dead cells [30].…”

MicroRNAs interfere with DNA methylation in rheumatoid arthritis synovial fibroblasts

“…Betaine inhibited the proliferation of synovial fibroblasts and SW982 sarcoma cells, but not of HepG2 cells, a hepatic tumour cell line that lost the ability to produce BHMT. 4 This showed that hepatocytes and synovial fibroblasts express BHMT, allowing a folate-independent methionine metabolism. Betaine, in contrast to L-methionine, decreased homocysteine levels.…”

“… 2 3 Betaine is involved in the remethylation of homocysteine to synthesise L-methionine, a pathway catalysed by betaine-homocysteine methyltransferase (BHMT). 4 L-methionine and betaine might represent strategies to reverse DNA hypomethylation locally in rheumatoid arthritis (RA) synovial tissue and systemically in peripheral T lymphocytes of patients with RA. 5 However, in RASF, the polyamine recycling pathway excessively consumes SAM, due to an increased expression of spermine/spermidine N1-acetyltransferase (SSAT1), thereby interfering with the DNA methylation process.…”