TY  - JOUR
T1  - O-GlcNAcylation of SPOP Controls Colorectal Cancer Development and Ferroptosis through Modulation of β-Catenin Degradation
A1  - Mateusz Piotr Kowalczyk
A1  - Tomasz Adam Piotrowski
A1  - Krzysztof Marek Nowak
JF  - Archive of International Journal of Cancer and Allied Science
JO  - Arch Int J Cancer Allied Sci
SN  - 3108-4834
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/ZJ2fVmjo1N
SP  - 137
EP  - 149
N2  - Therapeutic strategies for colorectal cancer (CRC) are often limited by recurrence and resistance to drugs. Ferroptosis, a recently characterized form of programmed cell death, represents a promising avenue for CRC treatment. Speckle-type POZ protein (SPOP), a substrate receptor of the E3 ubiquitin ligase complex CRL3, has a crucial biological role, yet its function in CRC therapy and ability to regulate ferroptosis remain largely unexplored. In this study, we demonstrate that SPOP acts as a tumor suppressor in CRC, suppressing tumor cell proliferation and metastasis while enhancing sensitivity to ferroptosis. Transcriptomic analyses indicated that the Wnt signaling pathway might serve as a potential downstream target of SPOP. Further investigations revealed that silencing SPOP led to elevated β-catenin protein levels, whereas clinical data showed an inverse correlation between SPOP expression and β-catenin levels. Mechanistic studies suggest that SPOP facilitates polyubiquitination and subsequent degradation of β-catenin at the K508 residue. Interestingly, O-GlcNAcylation of SPOP decreases its protein stability and diminishes its binding to β-catenin. Additionally, SPOP promotes CRC ferroptosis by suppressing the β-catenin/SLC7A11 axis. Co-treatment with the SPOP-targeting drug maprotiline and a ferroptosis inducer exhibited synergistic antitumor effects in CRC cell lines and xenograft models. Collectively, these results reveal the multifaceted role of SPOP in CRC and suggest that activating SPOP may enhance the efficacy of ferroptosis-based therapies.
UR  - https://smerpub.com/article/o-glcnacylation-of-spop-controls-colorectal-cancer-development-and-ferroptosis-through-modulation-of-qypyr9gjg0fwdhm
ER  -