Fat mass and obesity‐associated protein downregulation enhances N6‐methyladenosine methylation and drives ovarian cancer progression

TL;DR

Lower levels of the FTO protein increase RNA methylation and worsen ovarian cancer, suggesting FTO could be a new target for treatment.

Contribution

FTO is identified as a tumor suppressor in ovarian cancer through its regulation of m6A methylation and Ki67 expression.

Findings

FTO is downregulated in ovarian cancer tissues and cell lines compared to normal controls.

FTO overexpression inhibits tumor growth by reducing m6A methylation and modulating Ki67 expression.

Abstract

Ovarian cancer remains a major threat to women's health due to difficulties in early detection and limited treatment options. In this study, we investigate the role of FTO (fat mass and obesity‐associated protein), a key demethylase involved in N6‐methyladenosine (m6A) RNA modification, in the progression of ovarian cancer. Bioinformatics analysis of public datasets, along with validation in clinical samples, revealed that FTO expression was significantly lower in ovarian cancer tissues compared to normal controls. Functional assays demonstrated that FTO downregulation was associated with enhanced proliferation, migration, and invasion of ovarian cancer cells, which coincide with elevated global m6A methylation levels. Conversely, overexpression of FTO in vitro and in vivo significantly inhibited these tumorigenic phenotypes and suppressed tumor growth in a mouse xenograft model. Mechanistic studies demonstrated that FTO is localized in both the nucleus and cytoplasm and that its tumor‐suppressive effects are mediated, at least in part, through modulation of Ki67 expression. Together, these findings highlight FTO as a critical negative regulator of ovarian cancer progression and underscore the potential of targeting m6A methylation pathways as a therapeutic target. This research provides novel insights into the epitranscriptomic regulation of ovarian cancer and lays the groundwork for FTO‐based therapeutic development.

FTO downregulation elevates global m6A methylation, enhancing ovarian cancer malignancy. Bioinformatics and experimental analyses revealed that the fat mass and obesity‐associated protein (FTO) was significantly downregulated in ovarian cancer tissues and cell lines. Loss of FTO increased global m6A methylation, promoting tumor cell proliferation, migration, and invasion, whereas FTO overexpression reversed these effects both in vitro and in vivo. Mechanistically, FTO modulated m6A methylation–dependent regulation of proliferation‐associated proteins such as Ki67, thereby suppressing tumor growth in xenograft models. This study identifies FTO as a key negative regulator of ovarian cancer progression and highlights the therapeutic potential of targeting the m6A methylation pathway.

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