METTL3 affects FLT3-ITD+ Acute Myeloid Leukemia by mediating autophagy by regulating PSMA3-AS1 stability

Abstract

Objective The study was designed to explore the role of PSMA3-AS1 in initiation and progression of acute myeloid leukemia (AML) and investigate its action mechanism. Methods Expression of PSMA3-AS1, miR-20a-5p and ATG16L1 both in vitro and in vivo was measured by qRT-PCR. The expression of protein was detected by western blot assay. Edu staining and flow cytometry were utilized to measure cell proliferation and apoptosis. Potential target was predicted by bioinformatics and was verified by dual-luciferase report gene assay and RNA pull 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 METTL3 on PSMA3-AS1. Tumor model was used to identify the effect of PSMA3-AS1 on tumor growth in vivo, and immunohistochemistry was applied to detect expression of ki67 and TUNEL. Results The results indicate that PSMA3-AS1 was upregulated in FLT3-ITD + AML patients. Si-PSMA3-AS1 can inhibit the proliferation, autophagy and inhibit the apotosis in MV4-11 cells. METTL3 could enhances the PSMA3-AS1 RNA stability. In addition, this study revealed that PSMA3-AS1 affected FLT3-ITD + AML by targeting expression of miR-20a-5p, and miR-20a-5p further modulated expression of ATG16L1, an mRNA that down-regulated in AML, to affect disease advancement. Conclusion PSMA3-AS1 could promote FLT3-ITD + AML progression by regulating the level of autophagy through the miR-20a-5p/ATG16L1 pathway. In addition, the increase of PSMA3-AS1 may be caused by the involvement of METTL3 in regulating its stability. This discovery will provide new horizons for early screening and targeted therapy of FLT3-ITD + AML.

METTL3's role in cervical cancer development through m6A modification

“…Through RNA-seq and MeRIP-seq analyses, we identified a prominent m 6 A site in the 3′UTR of PDE3A mRNA. Silencing METTL3 significantly downregulated the methylation peak of this site, indicating that METTL3 mediates m 6 A modification of the adenosine in the GGACC sequence of the PDE3A 3′UTR, potentially leading to PDE3A mRNA degradation. Mechanistic experiments demonstrated that METTL3 regulates m 6 A methylation at the A residue within the GGACC motif of the PDE3A 3′UTR.…”

“…Only PDE3A a notably high enrichment (≥2000), warranting further investigation. MeRIP-seq revealed that the consensus motif of METTL3 was recognized during m 6 A modification (GGACC) of the 3′ untranslated region (UTR) of PDE3A mRNA (Figure 7G). Therefore, PDE3A may be a potential target gene for METTL3-mediated m 6 A modification.…”

“…The m 6 A-mediated regulation of gene expression relies on reader proteins that recognize and bind to RNA molecules with m 6 A modifications. METTL3, the primary m 6 A writer, interacts with reader proteins, influencing transcript metabolism. For instance, in esophageal squamous cell carcinoma, 19 METTL3 increases the methylation level of EGR1 mRNA and enhances its stability in a YTHDF3-dependent manner.…”

“…5 Besides, the m 6 A gene also plays a crucial part in tumorigenesis and cancer progression. [6][7][8] m 6 A modifications significantly affect CC cell metastasis; however, the underlying mechanism remains unknown. Exploring the potential link between m 6 A modification and CC will expand our understanding of RNA modification-related processes and present innovative avenues for diagnosing CC.…”

“…m 6 A methylation functions in various physiological processes, including cell differentiation, circadian rhythm, and development. 5 Besides, the m 6 A gene also plays a crucial part in tumorigenesis and cancer progression. [6][7][8] m 6 A modifications significantly affect CC cell metastasis; however, the underlying mechanism remains unknown.…”