Targeting G9a Exerts Pleiotropic Suppression in Triple-Negative Breast Cancer Cells: Cooperatively Inducing Pyroptosis and Apoptosis

<b>Background:</b> Pyroptosis, a pro-inflammatory programmed cell death process, is a key player in tumor biology, including in triple-negative breast cancer (TNBC). Inhibiting G9a has been proven to exert anticancer effects; however, the molecular mechanism of the effects remains unclear. The study aimed to illustrate whether inhibiting G9a can suppress the process of TNBC cells by promoting pyroptosis and investigate the underlying mechanisms. <b>Methods:</b> MCF-10A, MDA-MB-231 and SUM159PT cell lines were used for in vitro study. CCK8 and EdU staining assay were used to examine the cell proliferation, and flow cytometry assay was performed to evaluate cell death. Inflammatory factors were measured by ELISA kits. The mRNA and protein expression levels were analyzed by qRT-PCR, Western blot, and immunofluorescence staining. Transmission electron microscopy was used to observe the morphological changes in cells. <b>Results:</b> We found that knockdown of G9a suppressed the growth and the abilities of invasion and migration, induced pyroptosis, and increased the expression of RIG-I, p-STAT1, and GSDME of TNBC. Furthermore, a RIG-I inhibition Cyclo (Phe-Pro) partially rescued the activation of pyroptosis enhanced by knockdown of G9a. <b>Conclusions:</b> These findings indicate that inhibiting the function of G9a induces pyroptosis in TNBC cells by the RIG-1/STAT1/GSDME pathway, which provides a new therapeutic target for TNBC treatment.