HACE1 suppresses cell migration, invasion, and chemoresistance in neuroblastoma by regulating the PKN1/PA2G4 axis.
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Neuroblastoma (NB), the most prevalent extracranial solid tumor in children, exhibits high mortality. This study investigated the function and underlying mechanisms of HACE1 in NB pathogenesis. NB tumor tissues and matched adjacent normal tissues were collected, and human NB cell lines SK-N-AS and SK-N-BE2 were used. Cell migration and invasion capacities were evaluated using wound healing and Transwell assays. Cell apoptosis was measured using TdT-mediated dUTP Nick-end Labeling staining. The HACE1 in vivo function was validated using a xenograft mouse model. The results demonstrated that HACE1 expression was downregulated in NB tissues compared with normal tissues. HACE1 overexpression suppressed chemoresistance, migration, and invasion in NB cells; mechanistically, HACE1 bound to PKN1 and promoted its destabilization. The effects of HACE1 knockdown were reversed by the co-knockdown of PKN1. Furthermore, PKN1 bound to and phosphorylated PA2G4 at the T261 residue. Functional assays demonstrated that overexpression of wild-type (WT) PA2G4 promoted cell migration, invasion, and chemoresistance, which were attenuated by the T261A mutation (a non-phosphorylation mimic) but further potentiated by the T261E mutation (a phosphorylation mimic). PKN1 overexpression enhanced the oncogenic functions of WT PA2G4 but not those of the T261A mutant. Finally, the anti-tumor effect of HACE1 was confirmed in vivo. Collectively, this study demonstrates that HACE1 suppresses NB cell migration, invasion, and chemoresistance by destabilizing PKN1, thereby preventing PKN1 from phosphorylating and activating PA2G4. Our findings elucidate a novel HACE1/PKN1/PA2G4 signaling axis in NB progression, expanding the understanding of NB pathogenesis and highlighting the axis's potential as a therapeutic target.