Nuclear Galectin-1 Drives Cancer Progression through O -GlcNAcylation-Dependent Regulation of SOX2.

Abstract

Galectin-1 is frequently upregulated in tumors and contributes to cancer progression. Here, we identify galectin-1 as a critical regulator of cancer stem-like properties. Silencing galectin-1 suppressed proliferation, motility, side population fraction, and tumorsphere formation in vitro , and impaired tumor initiation and growth in vivo , whereas overexpression enhanced these malignant phenotypes. Transcriptomic profiling revealed stemness-associated transcription factors as major downstream targets, with SOX2 emerging as a key effector. Galectin-1 knockdown reduced SOX2 expression, whereas overexpression increased SOX2 nuclear abundance and transcriptional activity. Rescue experiments demonstrated that SOX2 is functionally required for galectin-1-mediated stemness and tumorigenesis. Mechanistically, galectin-1 associates with SOX2 in an O -GlcNAcylation-dependent manner. Inhibition of O -GlcNAcylation or mutation of SOX2 O -GlcNAc sites disrupted this interaction, reduced SOX2 transcriptional activity, and impaired tumorsphere formation, supporting an intracellular lectin-like function. Structural modeling predicted that residues E71 and R73 within the carbohydrate recognition domain are critical for carbohydrate-mediated recognition of O -GlcNAc-modified SOX2, which was validated by mutagenesis. Clinically, galectin-1 was highly expressed in gastric tumors, correlated with advanced stage, and predicted poor prognosis. Notably, high co-expression of galectin-1 and SOX2 was significantly associated with unfavorable survival outcomes. These findings establish galectin-1 as a reader-like protein that functionally engages O -GlcNAcylated SOX2 and highlight the galectin-1/SOX2 axis as a potential therapeutic target in gastric cancer.