Epigenetically silenced DACT3 promotes tumor growth via affecting Wnt/beta-catenin signaling and supports chidamide plus azacitidine therapy in acute myeloid leukemia

Abstract

DACT gene is a potential Wnt antagonist and tumor suppressor gene. In this study, we first multidimensionally analyzed the expression of DACT gene in AML. Compared with DACT1 and DACT2, DACT3 was the most differentially expressed DACT family member in AML, suggesting that DACT3 plays the major role. The mRNA and protein expression levels of DACT3 were decreased and positively correlated in AML. In addition, down-regulation of DACT3 in AML was not completely dependent on promoter methylation, but also affected by histone deacetylation. We found that loss of DACT3 in AML is related to activation of Wnt signaling pathway. Furthermore, DACT3 inhibits the growth of AML cells in vitro and in vivo. Importantly, DACT3 improved the sensitivity of adriamycin in treating AML cells. Further research showed that co-treatment of chidamide and azacytidine up-regulates DACT3 expression and promotes cell apoptosis via inhibiting Wnt/β-catenin signaling in AML. Our data also shows that DACT3 is a candidate gene for therapeutic target and targeting DACT3 has the potential to validate the combination therapy of DNMT inhibitors and HDAC inhibitors.