Fat mass and obesity-associated protein (FTO)-induced upregulation of flotillin-2 (FLOT2) contributes to cancer aggressiveness in diffuse large B-cell lymphoma (DLBCL) via activating the PI3K/Akt/mTOR signal pathway.
Arch Biochem Biophys
; 758: 110072, 2024 08.
Article
en En
| MEDLINE
| ID: mdl-38914215
ABSTRACT
The role of fat mass and obesity-associated protein (FTO)-mediated N6-methyladenosine (m6A)-demethylation has been investigated in various types of cancers, but it is still unclear whether FTO participates in the progression of diffuse large B-cell lymphoma (DLBCL). Here, by conducting Real-Time qPCR and Western Blot analysis, we verified that FTO was especially enriched in the DLBCL cells (RCK-8, LY-3, DHL-6 and U2932) compared to normal WIL2S cells. Then, the overexpression and silencing vectors for FTO were delivered into the LY-3 and U2932 cells, and our functional experiments confirmed that silencing of FTO suppressed cell viability and division, and induced apoptotic cell death in the DLBCL cells, whereas FTO-overexpression exerted opposite effects. Further mechanical experiments showed that FTO demethylated m6A modifications in flotillin-2 (FLOT2) mRNA to sustain its stability for FLOT2 upregulation, and elevated FLOT2 subsequently increased the expression levels of phosphorylated PI3K (p-PI3K), p-Akt and p-mTOR to activate the tumor-initiating PI3K/Akt/mTOR signal pathway. Of note, FLOT2 also serve as an oncogene to enhance cancer malignancy in DLBCL, and the rescuing experiments showed that FTO-ablation induced suppressing effects on the malignant phenotypes in DLBCL were all abrogated by overexpressing FLOT2. Taken together, those data hinted that FTO-mediated m6A-demethylation upregulated FLOT2 to activate the downstream PI3K/Akt/mTOR signal pathway, leading to the aggressiveness of DLBCL, which potentially provided diagnostic, therapeutic and prognostic biomarkers for DLBCL.
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Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Regulación hacia Arriba
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Linfoma de Células B Grandes Difuso
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Fosfatidilinositol 3-Quinasas
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Proteínas Proto-Oncogénicas c-akt
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Serina-Treonina Quinasas TOR
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato
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Proteínas de la Membrana
Límite:
Humans
Idioma:
En
Revista:
Arch Biochem Biophys
Año:
2024
Tipo del documento:
Article