CircTADA2A inhibits cell proliferation and promotes ferroptosis by sponging miR-638 in acute myeloid leukemia.

Abstract

Dysregulation of circRNAs has been found to engage in the progression of many hematologic malignancies including acute myeloid leukemia (AML). In this study, we identified significantly downregulated circTADA2A, derived from linear transcriptional adaptor 2A (TADA2A) gene, in AML associated circRNAs microarrays using GEO2R tool. We aimed to elucidate the roles of circTADA2A in AML and the mechanisms involved. Quantitative reverse transcription PCR was used for verification of circTADA2A levels in AML specimens, and its diagnostic value and clinical significance were assessed. The effects of circTADA2A on proliferation and ferroptosis on THP-1 and HL-60 cells were carried out using cell counting kit-8, 5'-ethynyl-2'-deoxyuridine, Fe²⁺, lipid reactive oxygen species (ROS) and malondialdehyde (MDA) assays. Luciferase reporter, fluorescence in situ hybridization, RNA immunoprecipitation, and RNA pull-down assays were implemented to investigate the potential miRNAs that mediated circTADA2A functioning. We confirmed that circTADA2A levels were lowly expressed in plasma and bone marrow of AML patients, and associated with bone marrow blasts and cytogenetic risk. Plasma circTADA2A had a high sensitivity and specificity with an area under the curve value of 0.793 in differentiating AML patients from healthy individuals. THP-1 and HL-60 cells stably overexpressing circTADA2A exhibited reduced cell proliferation, and sensitized cell to ferroptosis by a ferroptosis inducer RSL3. Moreover, circTADA2A could counteracted Ferrostatin-1-induced inhibition of ferroptosis. Mechanistically, circTADA2A act as a sponge for miR-638, and upregulation of miR-638 expression could restore cellular phenotypes induced by circTADA2A. Our findings demonstrated that circTADA2A suppresses cell proliferation and promotes ferroptosis by sponging miR-638 during AML progression.