Ubiquitination‐Dependent LLGL2 Degradation Drives Colorectal Cancer Progression via THBS3 mRNA Stabilization

Abstract Colorectal cancer (CRC) is the second most common cause of cancer‐related deaths worldwide is highly associated with distant organ metastasis. Lethal(2) giant larvae protein homolog 2 (LLGL2) is often dysregulated in various tumors; however, the pathogenesis of CRC remains unclean. This study highlighted the tumor suppressor function of LLGL2 in CRC. Depleted LLGL2 exhibits the pro‐CRC effects. RNA sequencing reveals that LLGL2 suppresses CRC progression by inhibiting the phosphoinositide 3‐kinase (PI3K)‐protein kinase B (PKB)/Akt pathway. Further analysis using RNA immunoprecipitation sequencing and shotgun mass spectrometry indicated that LLGL2 primarily regulates the stability of thrombospondin 3 ( THBS3) mRNA by interacting with CCR4‐NOT transcription complex subunit 1 (CNOT1), thus inactivating the PI3K‐Akt pathway. Additionally, MDM2 acts as an upstream modulator of LLGL2 and promotes its degradation via the proteasomal pathway. This novel mechanism reveals potential therapeutic targets for CRC treatment and enhanced the understanding of how CRC progression can be controlled.