FTO Acts as a Suppressor Gene to Inhibit the Translation of KDM5A mRNA by Demethylating m6A Modifications in Lung Adenocarcinoma

Abstract

Background:

Fat mass and obesity-associated (FTO) protein, an m6A RNA demethylase, plays diverse roles in cancer, but its function in lung adenocarcinoma (LUAD) remains unclear.

Methods:

TCGA data analysis, clinical samples, and in vitro assays were used to assess FTO expression and function. Mechanistic studies, including RIP, meRIP, luciferase reporter, FISH, and ChIP assays, were performed to explore FTO-mediated regulation of KDM5A and downstream PTEN/PI3K/Akt signaling.

Results:

FTO was significantly downregulated in LUAD and associated with poor prognosis. Overexpression of FTO inhibited LUAD cell proliferation, invasion, and EMT. Mechanistically, FTO suppressed KDM5A protein translation by demethylating m6A sites, impairing YTHDF1-mediated recognition. Reduced KDM5A expression increased PTEN transcription via elevated H3K4me3, leading to PI3K/Akt inactivation. Rescue experiments confirmed KDM5A overexpression reversed the effects of FTO.

Conclusions:

FTO inhibits LUAD progression through an m6A-dependent FTO/YTHDF1/KDM5A/PTEN axis. These findings establish FTO as a tumor suppressor and potential therapeutic target in LUAD.