SPIB suppresses protective autophagy via the IFIT2/PINK1/Parkin axis to promote anoikis in colorectal cancer

BACKGROUND: Anoikis is a critical mechanism that suppresses tumor metastasis. However, cancer cells evade anoikis by activating protective autophagy, thereby promoting metastasis. Although SPIB acts as a tumor suppressor in multiple cancers, its role in regulating autophagy-mediated anoikis resistance in colorectal cancer (CRC) remains unclear. This study aimed to investigate the impact of SPIB on anoikis resistance in CRC cells. METHODS: Bioinformatics analysis was employed to screen key genes regulating anoikis resistance in CRC. Stable SPIB knockdown/overexpression cell lines were constructed, and in vitro/in vivo experiments were conducted to examine SPIB's biological functions in CRC. Mechanistic insights were obtained via CCK-8, EdU, Transwell, CUT&Tag-seq, RNA-seq, dual-luciferase reporter assays, and mitochondrial membrane potential assays. RESULTS: SPIB expression was significantly reduced in CRC tissues and cell lines. Functionally, SPIB inhibited CRC progression both in vitro and in vivo. Mechanistically, SPIB transcriptionally activated IFIT2, which subsequently restored mitochondrial membrane potential(ΔΨm), thereby inhibiting protective autophagy through the PINK1/Parkin pathway and sensitizing CRC cells to anoikis. CONCLUSION: Our results demonstrate that SPIB exerts tumor-suppressive effects during CRC invasion and metastasis through the IFIT2/PINK1/Parkin axis. This study highlights SPIB as a potential therapeutic target for overcoming anoikis resistance in CRC therapy.