5-Aza-2′-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer)

DNA methylation and histone acetylation are main epigenetic events regulating gene expression, serving as anticancer drug targets. A combination of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine with the histone deacetylase inhibitor depsipeptide synergistically induces apoptosis. To characterize genes involved in this process, we measured expression of 376 apoptosis-related genes with microarrays after treatment with the two inhibitors alone or in combination. The pro-apoptotic BIK (Bcl2-interacting killer) was the only gene synergistically upregulated in all four cancer cell lines tested (A549, PC-3, TK-10, and UO-31). BIK induction was confirmed by RT-PCR and Western blots. Histone acetylation of the BIK promoter region increased with depsipeptide treatment but was not further affected by 5-aza-2′-deoxycytidine. In summary, synergistic upregulation of pro-apoptotic BIK—previously shown to suppress tumor growth—appears to play a critical role in anticancer effects of 5-aza-2′-deoxycytidine plus depsipeptide.