The O-GlcNAc modification of PRRC2C at S2238 promotes SG formation and nasopharyngeal carcinoma metastasis

Purpose

Metastasis remains the leading cause of mortality in patients with nasopharyngeal carcinoma (NPC), yet its precise mechanism has not been fully elucidated.

Methods

In this study, we established high metastatic (HM) and low metastatic (LM) sublines of NPC cells using the Transwell system, aiming to systematically investigate the metabolic reprogramming events that occur during NPC metastasis.

Results

Metabolomics sequencing results revealed that HM NPC cells have undergone metabolic profile remodeling, leading to increased levels of O-linked N-acetylglucosamine (O-GlcNAc) modification substrates UDP-GlcNAc and UDP-GalNAc, consequently, HM cells exhibited a significantly higher global O-GlcNAc modification level than LM cells. Through the construction of OGT-overexpressing cells and O-GlcNAc modification sequencing, we identified a significant elevation in the O-GlcNAcylation level of Proline-Rich Coiled-Coil 2 C (PRRC2C), a protein associated with stress granule (SG) formation. By transfecting PRRC2C WT and PRRC2C S2238A (serine 2238-to-alanine substitution) plasmids, we mimicked the characteristics of HM and LM cells and found that the O-GlcNAc modification of PRRC2C at S2238 site could promote the formation of SG at mitochondrial platform. Mechanistically, NPC cells transfected with the PRRC2C S2238A plasmids maintained mitochondrial functional homeostasis, evidenced by intact mitochondrial membrane potential and balanced mitochondrial dynamics compared to PRRC2C WT cells. In the nude mice orthotopic transplantation model, the use of epigallocatechin gallate (EGCG) could modulate the metastatic potential of HM cells via the inhibition of SGs.

Conclusion

Collectively, this study identifies targeting O-GlcNAcylation of PRRC2C at S2238 and SG formation as a promising therapeutic strategy for patients with metastatic NPC.

Registry and the registration no. of the study/trial

N/A.