DNA damage-mediated FTO downregulation promotes CRPC progression by inhibiting FOXO3a via an m⁶A-dependent mechanism

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) show promise for castration-resistant prostate cancer (CRPC).
• N6-methyladenosine (m⁶A) modification is implicated in cancer progression and DNA damage response.
• The role of m⁶A regulators in CRPC remains largely unexplored.

Purpose of the Study:

• To investigate the role of Fat mass and obesity-associated protein (FTO) in prostate cancer (PCa).
• To explore the relationship between FTO, m⁶A, and response to PARPi in CRPC.

Main Methods:

• Analysis of m⁶A levels and FTO expression in PCa tissues.
• Functional studies involving FTO knockdown and overexpression in PCa cells.
• Investigation of FTO's downstream targets and regulatory mechanisms.
• Assessment of FTO's impact on PARPi efficacy in PCa models.

Main Results:

• Higher m⁶A levels and lower FTO expression correlated with unfavorable clinicopathological parameters in PCa.
• Reduced FTO promoted PCa growth, while FTO overexpression inhibited it.
• FTO downregulates FOXO3a expression in an m⁶A-dependent manner.
• DNA damage induces FTO degradation via ubiquitination.
• FTO overexpression enhanced the therapeutic effect of PARPi in PCa.

Conclusions:

• FTO plays a critical role in regulating PCa progression.
• The FTO/m⁶A/FOXO3a axis is a key mechanism in PCa.
• Targeting FTO may represent a novel therapeutic strategy to improve PARPi efficacy in CRPC.