METTL3 affects FLT3-ITD+ acute myeloid leukemia by mediating autophagy by regulating PSMA3-AS1 stability

Abstract

ABSTRACT The study was designed to explorethe role of PSMA3-AS1 in initiation and progression of acute myeloid leukemia(AML) and investigate its action mechanism. Expressionof PSMA3-AS1, miR-20a-5p and ATG16L1 both invitro and in vivo was measured byqRT-PCR. The expression of proteinwas detected by western blot assay. Edu staining and flow cytometry were utilizedto measure cell proliferation and apoptosis. Potential target was predicted bybioinformatics and was verified by dual-luciferase report gene assay and RNApull down assay. QRT-PCR was used to quantify autophagy (LC3, Beclin1, P62)related genes. The m6A modification test is used to verify the effect of METTL3on PSMA3-AS1. Tumor model was used to identify theeffect of PSMA3-AS1 on tumor growth invivo, and immunohistochemistry was applied to detect expression of ki67 andTUNEL. Theresults indicate that PSMA3-AS1 was upregulated in FLT3-ITD+AML patients. Si-PSMA3-AS1 could inhibit theproliferation, autophagy and promote the apoptosis in MV4-11 and Molm13 cells. METTL3 could enhance the PSMA3-AS1 RNA stability. In addition, this studyrevealed that PSMA3-AS1 affected FLT3-ITD+ AML bytargeting expression of miR-20a-5p, and miR-20a-5p further modulated expressionof ATG16L1, an mRNA that down-regulated in AML, to affect disease advancement. PSMA3-AS1 could promote FLT3-ITD+AML progression by regulating the level of autophagy through miR-20a-5p/ATG16L1pathway. In addition, the increase of PSMA3-AS1 may be caused by theinvolvement of METTL3 in regulating its stability. This discovery will providenew horizons for early screening and targeted therapy of FLT3-ITD+ AML.