Abstract
Oncofetal chondroitin sulfate expression plays an important role in the development of tumors and the pathogenesis of malaria in pregnancy. However, the biosynthesis and functions of these chondroitin sulfates, particularly the tissue-specific regulation either in tumors or placenta, have not been fully elucidated. Here, by examining the glycogenes availability in chondroitin sulfate biosynthesis such as xylosytransferase, chondroitin synthase, sulfotransferase, and epimerase, the conserved or differential CS glycosylation in normal, colorectal cancer (CRC), and placenta tissue were predicted. We found that the expression of seven chondroitin sulfate biosynthetic enzymes, namely B4GALT7, B3GALT6, B3GAT3, CHSY3, CHSY1, CHPF, and CHPF2, were significantly increased, while four other enzymes (XYLT1, CHST7, CHST15, and UST) were decreased in the colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) patients. In the human placenta, where the distinct chondroitin sulfate is specifically bound with VAR2CSA on Plasmodium parasite-infected RBC, eight chondroitin sulfate biosynthesis enzymes (CSGALNACT1, CSGALNACT2, CHSY3, CHSY1, CHPF, DSE, CHST11, and CHST3) were significantly higher than the normal colon tissue. The similarly up-regulated chondroitin synthases (CHSY1, CHSY3, and CHPF) in both cancer tissue and human placenta indicate an important role of the proteoglycan CS chains length for Plasmodium falciparum VAR2CSA protein binding. Interestingly, twelve highly expressed chondroitin sulfate enzymes were significantly correlated to worse outcomes (prognosis) in both COAD and READ. Furthermore, we showed that the levels of chondroitin sulfate enzymes are significantly correlated with the expression of immuno-regulators and immune infiltration levels in CRCs and placenta, and involved in multiple essential pathways, such as extracellular matrix organization, epithelial-mesenchymal transition, and cell adhesion. Our study provides novel insights into the oncofetal chondroitin sulfate biosynthesis regulation and identifies promising targets and biomarkers of immunotherapy for CRC and malaria in pregnancy.
Highlights
Glycosylation is the most frequent post-translational modification occurring in proteins and lipids, and is vital to cell adhesion and stability as well as cell-cell communication (Dennis et al, 1999)
We found that three chondroitin synthases (CHSY1, CHSY3, and CHPF) were upregulated in both cancer tissue and placenta, indicating an important role of Oncofetal CS (ofCS) chains length for VAR2CSA binding
The results indicated that the co-expression molecular of colon adenocarcinoma (COAD) were enriched in the extracellular matrix organization, extracellular matrix structural constituent, which was correlated with cell adhesion molecule binding
Summary
Glycosylation is the most frequent post-translational modification occurring in proteins and lipids, and is vital to cell adhesion and stability as well as cell-cell communication (Dennis et al, 1999). The assembly of linear or branched glycan chains is formed sequentially so that the product of an enzyme reaction prepares its acceptor as the substrate of the enzyme in the process (Glavey et al, 2015) Of these glycoenzymes, a small minority are involved in the CS biosynthesis pathway through the orchestration of enzymes’ kinetic properties and their compartmentalization in Golgi. Two homologous β4GalNAc-transferases, encoded by Csgalnact and Csgalnact, initiate CS synthesis, while chondroitin synthase and polymerizing enzyme, encoded by four homologous genes Chsy, Chsy, Chpf, and Chpf, are responsible for the elongation of the GalNAc-β 1-4GlcA-β 1-3 repeat backbone which determines the length of CS chains (Mikami and Kitagawa, 2013; Chen et al, 2018). The sulfation modification of CS is carried out by various sulfotransferase which catalyzes the transfer of a sulfate group to their respective sulfation sites on GalNAc, GlcA, or IdoA residues in CS chains (Mikami and Kitagawa, 2013)
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