KMT2D/ZNF460-induced COL9A1-mediated extracellular matrix stiffness maintains the cancer stem cell pool to promote colorectal cancer progression.

Collagen is a central component of the extracellular matrix (ECM) in tissues, and ECM can promote tumor cell immune evasion. Our research aimed to expound the biological function of the collagen alpha-1(IX) chain (COL9A1) in colorectal cancer (CRC) and the upstream mechanism regarding KMT2D/ZNF460. COL9A1 contributed to maintaining colorectal cancer stem cells (CCSC) self-renewal and proliferative capacity, and COL9A1 knockdown attenuated CCSC stemness, which was activated by 20.0 kPa polyacrylamide gels. Silencing of COL9A1 hampered tumor growth and stemness in mice induced by AOM/DSS and improved the tumor microenvironment (TME) in xenograft-bearing mice. Mechanistically, KMT2D promoted COL9A1 expression by mediating H3K4me1 modification of the enhancer and recruiting ZNF460. In the presence of attenuated KMT2D signaling, its effect on CCSC stemness and CRC progression was similar to that of knockdown of COL9A1, both of which have therapeutic benefits for CRC tumors. Again, the reactivation of COL9A1 reversed this trend. In conclusion, KMT2D mediates H3K4me1 modification of enhancers and recruits ZNF460 to activate COL9A1, which enhances ECM stiffness and self-renewal of CCSC to remodel TME, contributing to CRC progression.