2. Academic Validation
  3. Inhibition of polypeptide N-acetyl-α-galactosaminyltransferases is an underlying mechanism of dietary polyphenols preventing colorectal tumorigenesis

Inhibition of polypeptide N-acetyl-α-galactosaminyltransferases is an underlying mechanism of dietary polyphenols preventing colorectal tumorigenesis

  • Bioorg Med Chem. 2019 Aug 1;27(15):3372-3382. doi: 10.1016/j.bmc.2019.06.020.
Feng Liu 1,  Yalu Cui 1,  Fang Yang 1,  Zhijue Xu 1,  Lin-Tai Da 1,  Yan Zhang 2
Affiliations

Affiliations

  • 1 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
  • 2 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yanzhang2006@sjtu.edu.cn.
PMID: 31227364 DOI: 10.1016/j.bmc.2019.06.020
Abstract

Ellagitannin-derived ellagic acid (EA) and colonic metabolite urolithins are functional dietary ingredients for Cancer prevention, but the underlying mechanism need elucidation. Mucin-type O-glycosylation, initiated by polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAc-Ts), fine-tunes multiple biological processes and is closely associated with Cancer progression. Herein, we aim to explore how specific tannin-based Polyphenols affect tumor behavior of colorectal Cancer cells (CRC) by modulating O-glycosylation. Utilizing HPLC-based Enzyme assay, we find urolithin D (UroD), EA and gallic acid (GA) potently inhibit ppGalNAc-Ts. In particular, UroD inhibits ppGalNAc-T2 through a peptide/protein-competitive manner with nanomolar affinity. Computational simulations combined with site-directed mutagenesis further support the inhibitors' mode of action. Moreover, lectin analysis and metabolic labelling reveal that UroD can reduce cell O-glycans but not N-glycans. Transwell experiments prove that UroD inhibits migration and invasion of CRC cells. Our work proves that specific tannin-based Polyphenols can potently inhibit ppGalNAc-Ts activity to reduce cell O-glycosylation and lead to lowering the migration and invasion of CRC cells, suggesting that disturbance of mucin-type O-glycosylation is an important mechanism for the function of dietary Polyphenols.

Keywords

Colorectal cancer; Dietary polyphenol; O-glycosylation; Urolithin D; ppGalNAc-T.

Figures