Carbohydrate (Chondroitin 4) Sulfotransferase-11-Mediated Induction of Epithelial-Mesenchymal Transition and Generation of Cancer Stem Cells

Abstract

Introduction:We have previously shown that the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) is elevated in human breast cancer tissues, and that its expression in human breast cancer cell lines is associated with aggressive behavior of cells. The clinical significance of CHST11 expression is unknown, and its function in breast cancer cells is not fully understood. Objective: The current study was performed to define the clinical significance of this gene and address its biological function in promoting the aggressive behavior of breast cancer cells. Methods: Publicly available datasets were analyzed to determine the correlation of CHST11 expression with breast cancer survival. MCF-7 cells were transfected with the human CHST11 gene, and MCF-7-CHST11 cells with stable expression of the gene were established. Morphology and metastatic capacity of transfected cells were monitored in vitro. E-cadherin and β-catenin expression was compared by immunofluorescence. The expression of genes involved in epithelial-mesen-chymal transition (EMT) and pluripotency was determined using real-time PCR. The Wnt inhibitor, Wnt-C59, was used to examine the involvement of Wnt in CHST11-mediated morphology. Results: The elevated expression of CHST11 in breast tumor specimens was significantly associated with poor survival among patients. MCF-7-CHST11 cells displayed morphological characteristics consistent with EMT, together with a significantly higher proliferation rate, enhanced migratory potential, and more robust anchorage-independent growth. MCF-7-CHST11 cells showed decreased expression of E-cadherin and increased accumulation of β-catenin, as assessed by immunofluorescence. Consistently, increased expression of CHST11 resulted in upregulation of key EMT and stem cell markers. Morphological transition in MCF-7-CHST11 cells was partially reversed by co-incubation with an inhibitor of the Wnt pathway. Conclusions: Our findings support a role for CHST11 in induction of EMT and stem celllike properties. Our data also associate the expression levels of CHST11 in breast tumor specimens with patients' survival. The results have a significant implication for CHST11 expression level as a novel molecular signature for predictive and prognostic purposes in breast cancer. Moreover, with a possible role in driving tumor cell aggressiveness, CHST11 expression might be further considered as a potential therapeutic target for breast cancer.

The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance

“…Additionally, CS-A is an enzymatic substrate of CHST11, and it recruits different GFs and morphogens to guide neuron cell migration and bone and cartilage maturation in embryogenesis and bone and cartilage development, respectively [40] . Additionally, CHST11 drives breast cancer aggressiveness by inducing EMT and stem cell-like properties [41] . Besides CHST11 mRNA levels, the methylation status of this gene has potential as a prognostic biomarker in breast cancer [42] .…”

Secondary-Type Carbohydrate Modification as a Driver of Epithelial-Mesenchymal Transition and Features of Cancer Stem Cells

“…The observations by Behrens et al [11] not only reveal the potential of CHST11 as a potential drug target, but also support the view that public databases may play an increasingly important role for reverse translational research approaches in pharmacology [12]. While such databases often do not offer direct information on the expression of biologically relevant glycans, they can provide useful information on molecules involved in glycan biosynthesis [13].…”

“…In this issue of Pharmacology, Behrens et al [11] provide evidence for a role of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) in the induction of epithelial-mesenchymal transition and stem cell-like properties, at least partially involving the Wnt pathway [11]. While it is known that sulfation by CHST11 alters the function of chondroitin sulfate glycosaminoglycans, the authors found that transfection of the breast cancer cell line MCF-7 with the human CHST11 gene resulted not only in the expression of chondroitin sulfate A but also in the transition from a cobblestone-like to a spindle-like shape.…”

“…While such databases often do not offer direct information on the expression of biologically relevant glycans, they can provide useful information on molecules involved in glycan biosynthesis [13]. From the data published by Behrens et al [11] in this issue, it can be inferred that examination of…”

Cleavage of Syndecan-1 Promotes the Proliferation of the Basal-Like Breast Cancer Cell Line BT-549 Via Akt SUMOylation

“…In addition, the gene expression of C4ST-1 has been correlated with the progression of breast cancer ( Hazan et al, 2000 ). Most recently, Behrens et al (2020) reported a new role of C4ST-1 in the induction of epithelial–mesenchymal transition and stem cell-like properties in breast cancer. These aggressive tumor phenotypes are thought to be exerted via protein–sugar interactions that are defined by specific sulfation patterns generated by C4ST-1.…”