Aberrant genome-wide hypomethylation and long noncoding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. We previously found that SNHG6 lncRNA acted as an oncogene in hepatocarcinogenesis and could be considered a potential prognostic indicator for hepatocellular carcinoma (HCC). Here we verify that SNHG6 leads to genome-wide hypomethylation in hepatoma cells and that SNHG6 negatively correlates with the steady-state SAMe concentration in vivo and in vitro. SNHG6 suppressed MAT1A protein expression by activating the miR-1297/FUS pathway to regulate nucleocytoplasmic shuttling of MAT1A mRNA. In addition, SNHG6 promoted expression of MAT2A by suppressing direct binding of miR-1297 to the MAT2A 3'UTR. SNHG6 regulated steady-state SAMe levels via coupling of two miR-1297-mediated SAMe-dependent positive feedback loops. Interestingly, the effect of SNHG6 on genome-wide methylation was inhibited by exogenous SAMe within a certain concentration range. These results suggest that single lncRNA dysregulation can lead to aberrant genome-wide hypomethylation by inhibiting SAMe production in HCC and that exogenous SAMe may be beneficial in the treatment of HCC.