Platelet-derived exosomal LINC00183 facilitate colorectal cancer malignant progression driven by histone lactylation through stabilizing ENO1.

Platelets play a critical role in tumor progression across various cancers. However, little is known about the molecular mechanisms and biological roles of exosomal long non-coding RNAs (lncRNAs) produced from platelets in colorectal cancer (CRC). Using RNA sequencing, we identified LINC00183 as the most upregulated lncRNA in platelet-derived exosomes (PLT-Exos) from CRC patients, compared to healthy individuals. Analysis of CRC tissue microarrays and TCGA-CRC patient data indicated that LINC00183 is often overexpressed in CRC, in association with advanced tumor stage and poor survival. Effective transfer of exosomal LINC00183 to human CRC cells was verified by FISH, western blotting, and RT-qPCR analyses. Co-incubation with PLT-Exos from CRC patients and overexpression of LINC00183 stimulated the proliferative and invasive capacities of CRC cells. RNA pull-down and RNA immunoprecipitation assays revealed that LINC00183 interacts with enolase 1 (ENO1). This interaction rescues ENO1 from ubiquitin-proteasome-mediated degradation by masking a critical K262 residue. Co-immunoprecipitation, western blotting, CUT&Tag, and gene knockdown and overexpression assays further revealed that the LINC00183-ENO1 interaction activates glycolysis in CRC cells, leading to lactate accumulation, H3K18 lactylation, and transcriptional upregulation of the oncogene GDF15. These results highlight LINC00183 as a possible therapeutic target for CRC.