Lysine crotonylation (Kcr) is elevated in colorectal cancer (CRC) tissues, yet its functional significance in disease progression remains unclear. This investigation aimed to determine the specific contribution and molecular pathway of crotonylation at lysine 27 on histone H3 (H3K27cr) in driving CRC metastasis. Immunohistochemical staining was applied to assess the relationship between H3K27cr expression and metastatic features in CRC. Loss-of-function and gain-of-function experiments were carried out both in vitro and in vivo to evaluate the impact of LINC00922 on CRC metastatic potential. Single-cell RNA sequencing combined with immunoprecipitation-based approaches was used to delineate how LINC00922 influences CRC metastasis by modulating H3K27cr. In clinical specimens, H3K27cr was markedly increased in metastatic CRC tissues and showed a strong positive association with more advanced disease stages. Functionally, depletion of LINC00922 substantially reduced the migratory ability of CRC cells in culture and in animal models. Notably, supplementation with NaCr reversed the impaired migration and invasion observed in LINC00922-deficient cells by restoring H3K27cr levels. At the mechanistic level, LINC00922 stimulated cellular invasion and motility by enhancing H3K27cr-dependent expression of cell adhesion molecules (CAMs) within epithelial cells. Importantly, LINC00922 bound to sirtuin 3 (SIRT3) and interfered with its association at the ETS1 promoter. Consequently, this interaction increased H3K27cr enrichment at the ETS1 promoter, thereby upregulating ETS1 transcriptional activity. The present work identifies a previously unrecognized mechanism whereby H3K27cr, under the control of LINC00922, promotes metastatic spread in CRC. These insights advance current understanding of histone crotonylation’s role in CRC metastasis.
