Metastatic prostate cancer continues to pose a difficult therapeutic challenge. Prostate cancer progression is associated with aberrant O glycosylation of cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous metastasis of human prostate cancer xenografts that express high levels of galectin 4 along with genetic signatures of EGFR HER2 signaling and O glycosylation. Galectin 4 expression in clinical specimens of prostate cancer correlated with poor patient survival. Galectin 4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin, and Twist1, and lowered expression of E cadherin, thereby facilitating epithelial- mesenchymal transition, invasion, and metastasis. In vivo investigations established that galectin 4 expression enabled prostate cancer cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin 4 relied upon O glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin 4 and O glycosylation triggered aberrant receptor signaling and more aggressive invasive character in prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin 4 and C1GALT1 mediated glycosylation in a signaling axis that is activated during prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease.