Schematic summary of the dysregulation of SMAD1 expression by promoter hypermethylation and the consequences for DLBCL survival and growth. In both subtypes of DLBCL, the promoter region of SMAD1 is recurrently hypermethylated, which causes SMAD1 gene repression. Repression of SMAD1 blocks the tumor-suppressive TGF-β/SMAD1/S1PR2 pathway. Loss of S1PR2 expression within the germinal center promotes B-cell proliferation and prevents S1P-driven apoptosis. DAC demethylates SMAD1 and restores SMAD1 expression, allowing its phosphorylation upon TGF-β binding and its translocation into the nucleus, followed by S1PR2 expression, as well as a reduction in the tumor burden in experimental settings.