The cytokine-cosmc signaling axis upregulates the tumor-associated carbohydrate antigen Tn

Abstract

Tn antigen (GalNAc-α-O-Ser/Thr), a mucin-type O-linked glycan, is a well-established cell surface marker for tumors and its elevated levels have been correlated with cancer progression and prognosis. There are also reports that Tn is elevated in inflammatory tissues. However, the molecular mechanism for its elevated levels in cancer and inflammation is unclear. In the current studies, we have explored the possibility that cytokines may be one of the common regulatory molecules for elevated Tn levels in both cancer and inflammation. We showed that the Tn level is elevated by the conditioned media of HrasG12V-transformed-BEAS-2B cells. Similarly, the conditioned media obtained from LPS-stimulated monocytes also elevated Tn levels in primary human gingival fibroblasts, suggesting the involvement of cytokines and/or other soluble factors. Indeed, purified inflammatory cytokines such as TNF-α and IL-6 up-regulated Tn levels in gingival fibroblasts. Furthermore, TNF-α was shown to down-regulate the COSMC gene as evidenced by reduced levels of the COSMC mRNA and protein, as well as hypermethylation of the CpG islands of the COSMC gene promoter. Since Cosmc, a chaperone for T-synthase, is known to negatively regulate Tn levels, our results suggest elevated Tn levels in cancer and inflammation may be commonly regulated by the cytokine-Cosmc signaling axis.

Overexpression of Cosmc suppresses cell migration and invasion in different subtypes of breast cancer cells via Tn and T glycans

“…Additionally, overexpression of Tn antigen has been found in BC and its expression is associated with the increased migratory potential of the MDA-MB-231 BC cell line [23]. It has also been reported that the levels of Tn antigen are negatively regulated by Cosmc and, furthermore, an elevation of Tn levels in cancer along with inflammation may be modulated via the cytokine-Cosmc signaling axis [24]. Thus, the regulation of Cosmc in balance of Tn-T antigen is associated with multiple cancers.…”

Differential expression of Cosmc, T-synthase and mucins in Tn-positive colorectal cancers

“…In patients, cancer cells grow in a microenvironment influenced by the oxygen level, cytokines, cellular polarity, and stromal contact. Recent studies showed that cytokine-initiating signaling may regulate the Tn antigen, and hypoxia promotes the STn antigen in bladder cancer [ 46 , 47 ]. In addition, hypoxia also up-regulates the transcription of UGT-1 in CRC cells, which transports UDP-Gal and probably UDP-GalNAc, suggesting that hypoxia may affect nucleotide sugar pools to modulate glycosylation [ 48 , 49 ].…”

Translation of genome to glycome: role of the Golgi apparatus

“…The best‐known example of this proteostatic mechanism is the regulation of the levels of T‐synthase (C1GALT1) involved in O‐glycan biosynthesis by the co re 1 β3‐Gal‐T– s pecific molecular c haperone (COSMC; also known as C1GALT1‐specific chaperone 1, C1GALT1C1). The reduction in active COSMC due to mutations or expression changes leads to ER retention and degradation of T‐synthase and alterations in O‐glycans . The proteostasis of GTs that overcome ER quality control and reach the Golgi is regulated by both active and passive processes.…”