Epigenetically Silenced DACT3 Promotes Tumor Growth Via Wnt/Β-Catenin Signaling And Supports Azacytidine Plus Chidamide Therapy In Acute Myeloid Leukemia

Abstract

DACT is a potential Wnt antagonist and tumor suppressor gene, however, its role in acute myeloid leukemia (AML) remains unknown. In this study, DACT3 was identified as playing a critical role in AML compared with DACT1 and DACT2. 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, and the co-treatment showed a promising therapeutic prospects in FLT3-mutant AML. Our data shows that targeting DACT3 has the potential to validate the combination therapy of DNMT inhibitors and HDAC inhibitors.

Note:
Funding Information: This study was supported by National Natural Science Foundation of China (Grant No. 81570117).

Declaration of Interests: The authors declare that they have no conflicting financial interests

Ethical Approval Statement: The study was approved by the Institutional Ethics Committee of the Third Xiangya Hospital of Central South University. Informed consent from patients or their legal guardians were obtained according to the Declaration of Helsinki. Animal experiments were approved by the Institutional Animal Care and Use Committee of Central South University.

Keywords: DACT3, acute myeloid leukemia, Wnt/β-catenin signaling, methylation, epigenetic therapy