O-GlcNAc-induced nuclear translocation of hnRNP-K is associated with progression and metastasis of cholangiocarcinoma

Mol Oncol. 2019 Feb;13(2):338-357. doi: 10.1002/1878-0261.12406. Epub 2019 Jan 10.


O-GlcNAcylation is a key post-translational modification that modifies the functions of proteins. Associations between O-GlcNAcylation, shorter survival of cholangiocarcinoma (CCA) patients, and increased migration/invasion of CCA cell lines have been reported. However, the specific O-GlcNAcylated proteins (OGPs) that participate in promotion of CCA progression are poorly understood. OGPs were isolated from human CCA cell lines, KKU-213 and KKU-214, using a click chemistry-based enzymatic labeling system, identified using LC-MS/MS, and searched against an OGP database. From the proteomic analysis, a total of 21 OGPs related to cancer progression were identified, of which 12 have not been previously reported. Among these, hnRNP-K, a multifaceted RNA- and DNA-binding protein known as a pre-mRNA-binding protein, was one of the most abundantly expressed, suggesting its involvement in CCA progression. O-GlcNAcylation of hnRNP-K was further verified by anti-OGP/anti-hnRNP-K immunoprecipitations and sWGA pull-down assays. The perpetuation of CCA by hnRNP-K was evaluated using siRNA, which revealed modulation of cyclin D1, XIAP, EMT markers, and MMP2 and MMP7 expression. In native CCA cells, hnRNP-K was primarily localized in the nucleus; however, when O-GlcNAcylation was suppressed, hnRNP-K was retained in the cytoplasm. These data signify an association between nuclear accumulation of hnRNP-K and the migratory capabilities of CCA cells. In human CCA tissues, expression of nuclear hnRNP-K was positively correlated with high O-GlcNAcylation levels, metastatic stage, and shorter survival of CCA patients. This study demonstrates the significance of O-GlcNAcylation on the nuclear translocation of hnRNP-K and its impact on the progression of CCA.

Keywords: O-GlcNAcylated proteins; bile duct cancer; heterogeneous nuclear ribonucleoprotein-K; metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Duct Neoplasms / metabolism*
  • Bile Duct Neoplasms / pathology*
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Nucleus / metabolism*
  • Cell Proliferation
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / pathology*
  • Disease Progression*
  • Female
  • Glucosamine / metabolism*
  • Glycosylation
  • Heterogeneous-Nuclear Ribonucleoprotein K / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Protein Transport
  • Treatment Outcome


  • Biomarkers, Tumor
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Glucosamine