Kinesin Family Member 26A Disrupts DNA-Dependent Protein Kinase Complex Formation to Enhance Chemoradiotherapy...

Chemoradiotherapy is the principal approach for treating a wide range of human cancers. However, its therapeutic outcomes in clinical settings are frequently impaired by resistance to tumor chemoradiotherapy. In this study, we demonstrated that kinesin family member 26A (KIF26A) is downregulated in chemoradioresistant colorectal cancers, as revealed by transcriptomic analyses of colorectal cancer tissues and cell lines. Reduced KIF26A levels predicted diminished responsiveness to chemoradiotherapy and unfavorable outcomes in patients with colorectal cancer. Furthermore, lower KIF26A expression was associated with colorectal cancer (CRC) progression, migration, and invasion. This is the first demonstration that KIF26A interacts with Ku70 to suppress the formation of the DNA-dependent protein kinase (DNA-PK) complex, thereby preventing activation of non-homologous end joining (NHEJ) for repairing DNA damage. This makes cancer cells more vulnerable to DNA damage from chemoradiotherapy, thereby enhancing their sensitivity. To address chemoradio-resistance in KIF26A-low-expressing cells, we ascertained that histone deacetylase inhibitors (HDACi) could enhance acetylation of the KIF26A promoter, upregulate KIF26A, and boost the sensitivity of chemoradiotherapy-resistant cells. Thus, our research elucidates the function of KIF26A in the NHEJ repair process and indicates that combining HDACi with chemoradiotherapy may serve as a promising therapeutic modality for colorectal cancer.