# O-GlcNAcylation of SPOP regulates colorectal cancer progression and ferroptosis by mediating β-catenin degradation

## TL;DR

This study shows that SPOP, a protein involved in cell regulation, can suppress colorectal cancer by promoting cell death and reducing cancer spread.

## Contribution

The study reveals that SPOP regulates β-catenin degradation and ferroptosis in colorectal cancer through O-GlcNAcylation.

## Key findings

- SPOP acts as a tumor suppressor by inhibiting CRC cell proliferation and metastasis.
- O-GlcNAcylation of SPOP affects its stability and interaction with β-catenin, modulating ferroptosis.
- Combining SPOP-targeted drugs with ferroptosis inducers shows synergistic antitumor effects in CRC.

## Abstract

Current therapeutic approaches for colorectal cancer (CRC) face challenges such as recurrence and drug resistance. Ferroptosis, a novel form of cell death, is a promising therapeutic approach for CRC. SPOP plays an important biological role as a substrate-binding protein of the E3 ubiquitin ligase complex CRL3, but its therapeutic effects in CRC patients and its ability to modulate ferroptosis remain largely unknown. This study demonstrated that SPOP functions as a tumor suppressor in CRC and that SPOP inhibits the proliferation and metastasis of CRC cells and increases their sensitivity to ferroptosis. Transcriptome analysis suggested that Wnt signaling may be a potential target for the function of SPOP. Further data revealed that SPOP knockdown increased β-catenin protein levels, and the clinical data indicated that SPOP expression had the opposite effect on β-catenin protein levels. Molecular biology experiments suggest that SPOP promotes polyubiquitination and degradation of the K508 site of β-catenin. Interestingly, O-GlcNAcylation of SPOP reduces its protein stability and affects SPOP binding to β-catenin, and SPOP also promotes CRC ferroptosis by inhibiting the β-catenin/SLC7A11 axis. Combined treatment with the SPOP-targeted drug maprotiline and a ferroptosis inducer has synergistic antitumor efficacy in CRC cells and xenografts. Our study reveals the multifaceted function of SPOP in CRC, and the activation of SPOP may be a feasible strategy to increase the sensitivity of CRC to ferroptosis inducers.