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

Abstract

AbstractBackgroundDACT gene is a potential Wnt antagonist and tumor suppressor gene. However, the expression of DACT gene in acute myeloid leukemia (AML) and its role are still unknown.MethodsIn this study, we first multidimensionally analyzed the expression of DACT gene in AML through RNA seq, qRT-PCR and Western blotting analysis as well as TCGA database analysis. Then DACT3 was identified as playing a critical role in AML, and its clinical significance was further explored. The molecular mechanism of DACT3 down-regulation in AML from aspects of DNA methylation and histone acetylation were inquired. Finally, the biological functions of DACT3 in AML were investigated by cell modelsin vitroand animal experimentsin vivo.ResultsCompared 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 significantly decreased and positively correlated in AML. Moreover, low expression of DACT3 is associated with no remission disease status and poor prognosis in AML patients. 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 cellsin vitroand in severe immunodeficiency (SCID) mice. 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, suggesting a promising therapeutic prospects in FLT3-mutant AML.ConclusionThis is the first study revealing the epigenetic regulatory molecular mechanism of the down regulated expression of DACT3 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.