CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis.

Chromobox homolog 2 (CBX2), a component of the polycomb repressive complex 1, is overexpressed in various cancers, but its specific role in colorectal cancer (CRC) is not fully understood. This study aimed to characterize the functional and regulatory roles of CBX2 in CRC. Tissue microarray analysis revealed the elevated CBX2 levels in tumor compared to adjacent normal tissues, which is significantly correlated with poor prognosis. Gain and loss of function studies demonstrated that CBX2 significantly promoted CRC progression and chemoresistance in cell lines, patient-derived CRC organoids and xenografts. In the AOM/DSS mouse model, treatment with the innovatively-developed cy5-PBAE/siCBX2 nanoparticle significantly reduced tumor aggressiveness. Mechanistic studies unveiled that the transcription factor RUNX1 is the positive regulator of CBX2. RNA-seq, ATAC-seq and CUT & RUN results indicated CBX2 knockdown induced epigenetic changes, especially alterations in chromatin accessibility. Moreover, we further identified MAP4K1 as a target gene of RUNX1-CBX2, with significant clinical and prognostic relevance in CRC. Collectively, these findings suggest the pivotal role of RUNX1-CBX2-MAP4K1 axis in CRC progression and underscore CBX2 as a promising biomarker and therapeutic target. The regulatory function of CBX2 on chromatin accessibility and the role of the RUNX1-CBX2-MAP4K1-pERK axis in the progression of colorectal cancer.