HOXC8 impacts lung tumorigenesis by preventing pyroptotic cell death through the suppression of caspase-1 expression.

Homeobox C8 (HOXC8) is a transcription factor preferentially overexpressed in a large percentage of non-small cell lung carcinoma (NSCLC). To investigate the function of HOXC8 in NSCLC, we showed that knockdown of HOXC8 led to massive NSCLC cell death in a mechanism of pyroptosis because both YVAD, a caspase-1 (CASP1) inhibitor, and disulfiram, which prevents gasdermin D (GSDMD) pore formation, blocked cell death caused by HOXC8 depletion. Intriguingly, ASC, a key component of canonic inflammasome, was dispensable for pyroptosis occurring in HOXC8-depleted cells. Instead, we detected greatly elevated levels of both CASP1 protein and mRNA in HOXC8-knockdown cells. As forced expression of CASP1 is sufficient to induce CASP1 activation and pyroptosis, we reason that pyroptosis led by HOXC8 depletion results from massive increase in the abundance of CASP1. To uncover the functional connection between HOXC8 and CASP1 expression, we revealed that HDAC1/2 was involved in augmented CASP1 transcription induced by HOXC8 knockdown. Moreover, we found that HOXC8 and HDAC1 were in the same immunocomplex and the presence of HOXC8 is required for the recruitment of HDAC1 to CASP1 promoter. Since HOXC8 also binds CASP1 promoter, we conclude that HOXC8 negatively regulates CASP1 expression by drafting HDAC1/2 to CASP1 gene. Finally, we demonstrated that cholesterol-conjugated HOXC8 siRNA was able to slow down NSCLC tumorigenesis. This study suggests that HOXC8 participates NSCLC development by controlling CASP1 expression and pyroptosis.