O-Glycosylation-mediated signaling circuit drives metastatic castration-resistant prostate cancer

Castration resistance and metastasis are both characteristics of prostate cancer (PCa) progression. Our study indicated that higher levels of galectin-4, surface sialylated and unsialylated core 1 O-glycans, and the sugar nucleotide donors for the involved glycosyltransferases are expressed in castration-resistant and metastatic PCa in correlation with poor overall survival in patients. Therefore, our research invents methods to identify a subtype of high-risk PCa comprising approximately 16% of all patients received surgical care. PCa patients of this subtype should be actively treated with targeted therapies tailored to the cognate tumors. Conversely, patients with PCa negative for these biomarkers predicted as indolent tumor do not need aggressive treatments. As galectin-4 initiated RTKs signaling will activate MYC via ERK and drive MYC-dependent biosynthesis of more galectin-4 ligands, this way amplifies the RTKs signaling. MYC reprograms abnormal O-glycosylation pathway leading to modification of RTKs with α2,3-sialyl T antigen, encoding for the galectin-4 binding. The lectin-carbohydrate interaction activates RTKs and initiates downstream signaling cascades to promote PCa progression. High-level expression of galectin-4 and C1GALT1 predicts worse survival rate than either single marker diagnosis. Malignant transformation is connected with changes of glycosylation that modifies membrane proteins at cell surface including RTKs, which is now revealed as promoting the invasive and metastatic behaviors of PCa cells. PCa patients with high PSA and high levels of UDP-GlcNAc, UDP-GalNAc, UDP-Gal, CMP-sialic acid, proteins conjugated with sialylated and unsialylated core 1 O-glycans, and galectin-4 are predicted to progress fast on androgen-deprivation therapy and develop metastases. Biochemical assays can be applied to determine the levels of galectin-4 protein, proteins conjugated with sialylated and unsialylated core 1 O-glycans, and nucleotide sugars, such as UDP-GlcNAc, UDP-GalNAc, UDP-Gal and CMP-sialic acid in urine and serum. One can use ion-pair reverse-phase HPLC, LC-MS/MS, and antibodies or sialylated core 1 O-glycan that specifically recognize galectin-4 to detect the subjects of these nominated biomarkers. Furthermore, patients diagnosed with these features are suggested to be treated with inhibitors that downregulate MYC or SOX9 expression in the PCa.
Pei-Wen Hsiao

 

Co-researchers:Sheue-Fen Tzeng, Chin-Hsien Tsai, Tai-Kuang Chao, Yu-Ching Chou, Yu-Chih Yang, Mong-Hsun Tsai, Tai-Lung Cha, and Pei-Wen Hsiao