SIRT1-mediated deacetylation stabilizes cortactin to enhance glycolysis and drive cervical cancer progression

Cervical cancer is a major cause of cancer-related death among women worldwide. Although cortactin (CTTN) has been implicated in tumor progression, its regulatory mechanisms and functional relevance in cervical cancer remain unclear.

CTTN expression in tissues and cell lines was examined by qRT-PCR, western blotting, and immunohistochemistry. Gain- and loss-of-function studies were performed to evaluate the role of CTTN in cell proliferation, colony formation, migration and invasion. Seahorse assays and biochemical analyses were used to assess the effects of CTTN on aerobic glycolysis. CTTN-SIRT1 interaction was examined by immunofluorescence and co-immunoprecipitation. Metabolic reprogramming was analyzed by qRT-PCR, western blotting of glycolytic enzymes, glucose uptake and lactate production assays, and Seahorse XF analysis. Rescue experiments were conducted to determine the dependence of SIRT1 activity on CTTN. Xenograft models were established to examine in vivo tumorigenesis.

CTTN was significantly upregulated in cervical cancer tissues and cell lines. CTTN silencing suppressed cell proliferation, colony formation, migration, invasion, and glycolysis, whereas CTTN overexpression enhanced these phenotypes. Mechanistically, SIRT1 interacts with and deacetylates CTTN, thereby stabilizing cortactin protein expression. SIRT1 knockdown reduced cortactin levels and suppressed tumor cell growth and glycolytic activity, whereas ectopic expression of CTTN rescued these effects. In vivo, inhibition of either SIRT1 or CTTN significantly reduced tumor volume, weight, and Ki-67 expression.

SIRT1 stabilizes cortactin through deacetylation, promoting aerobic glycolysis and malignant progression in cervical cancer. Targeting the SIRT1-CTTN axis may be a promising therapeutic strategy for cervical cancer.