The Effect of O-GlcNAcylation on hnRNP A1 from Colorectal Cancer

The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) isoform, which is a member of hnRNP A/B subfamily, was found to be over expressed in almost all examined human colorectal cancer as well as lung cancer tissues. It is one of the major pre-mRNA binding proteins and is involved in telomere lengthening, cell signaling and tumor development. Furthermore, it is involved in regulating gene expression at both transcriptional and translational levels. Although hnRNP A1 is predominantly nuclear, it shuttles rapidly between the nucleus and the cytoplasm, assisted by the translocation protein transportin1, and plays its different roles in accordance to its location. HnRNP A1 translocation is regulated partially through phosphorylation on serine residues at its c-terminal domain. Recently, we have shown that in addition to phosphorylation, hnRNP A1 is also modified by O-linked N-acetylglucosaminylation (O-GlcNAcylation). We also confirmed the association of hnRNP A1 with transportin1 and found that O-GlcNAcylation affects this interaction. We have shown that induced phosphorylation¬ of hnRNP A1 leads to accumulation of both hnRNP A1 and transportin1 in the cytosol of colorectal cancer cells. However, elevated O-GlcNAcylation levels of hnRNP A1 counteract the phosphorylation effect. Phosphorylation and O-GlcNAcylation may compete on the same serine or threonine residues. In addition, one modification could interrupt the other when residing on adjacent sites. Such counter interplay between these modifications could influence the translocation of the protein by transportin1 as well as its function or stability.

Mapping hnRNP A1 O-GlcNAcylation sites and elucidation of their effect on hnRNP A1 function and its interaction with transportin1 are under investigation. This research will significantly contribute to the understanding of hnRNP A1 in cell physiology and cancer development.