In an effort to elucidate molecular mechanism underlying caspase-1 protein accumulation, we revealed that knockdown of HOXC8 increased the level of caspase-1 mRNA and the occupancy of RP-II in the CASP1 promoter while not altering the activity of CASP1 promoter reporter plasmid, suggesting that HOXC8 represses CASP1 transcription through a histone-involved epigenetic mechanism in lung cancer cells. Here, HOXC8 is linked to lung cancer.