# Loss of UFL1 confers enzalutamide resistance of prostate tumors by regulating METTL16-mediated m6A modification of EEF1A1 mRNA

## TL;DR

This study shows that loss of UFL1 makes prostate tumors resistant to enzalutamide by altering mRNA modifications, offering a new target for treatment.

## Contribution

The study identifies a novel UFL1-METTL16-EEF1A1 pathway that drives resistance to enzalutamide in prostate cancer.

## Key findings

- UFL1 deficiency increases resistance to enzalutamide in prostate cancer cells and xenograft models.
- Loss of UFL1 stabilizes METTL16, leading to m6A modification of EEF1A1 mRNA and increased EEF1A1 protein levels.
- The UFL1-METTL16-EEF1A1 pathway activates the m6A-IGF2BP1 axis, promoting resistance to apoptosis.

## Abstract

Enzalutamide (ENZ), a next-generation androgen receptor (AR) inhibitor, is a cornerstone treatment for metastatic prostate cancer. However, resistance to ENZ inevitably develops in these patients, and the mechanisms underlying this resistance remain poorly understood. This study reveals that UFL1 is dysregulated in ENZ-resistant cells, xenograft models, and prostate tumors. UFL1 deficiency enhances prostate cancer cell resistance to ENZ both in vitro and in vivo. Mechanistically, UFL1 loss decreases METTL16 UFMylation, thereby reducing its ubiquitination level and increasing its protein stability. Additionally, METTL16-mediated m6A modification of EEF1A1 mRNA activates the m6A-IGF2BP1 axis, resulting in increased EEF1A1 protein levels and enhanced resistance to ENZ-induced apoptosis. These findings uncover a novel UFL1-METTL16-EEF1A1 signaling pathway that drives ENZ resistance, suggesting that targeting this cascade may offer a promising therapeutic strategy for overcoming ENZ resistance in prostate cancer.