Cytoplasmic SIRT1 enhances the stemness of polyploid giant cancer cells by promoting β-catenin protein stability and nuclear accumulation in ovarian carcinoma upon neoadjuvant chemotherapy

Abstract

Epithelial ovarian carcinoma, the deadliest gynecological malignancy, frequently develops treatment resistance through polyploid giant cancer cells (PGCCs) that typically emerge after carboplatin-paclitaxel chemotherapy. Accumulating evidence suggests that PGCCs exhibit traits similar to those of cancer stem cells (CSCs), including expression of stemness markers, self-renewal, and resistance to treatment. Although Wnt/β-catenin signaling is a major driver of stemness and chemoresistance in ovarian carcinoma, the specific mechanisms by which it activates cancer stemness of PGCCs remain unclear. This study investigates the role of SIRT1-mediated deacetylation of β-catenin in PGCC stemness, with a specific focus on SIRT1's subcellular localization. Immunohistochemical analysis of ovarian carcinoma samples from patients receiving neoadjuvant chemotherapy revealed that nuclear β-catenin staining in PGCCs correlated with SOX2-positive expression. Comparative proteomics further demonstrated the enrichment of differentially expressed proteins related to the Wnt pathway and stem cell programs in PGCCs compared to diploid tumor cells, highlighting the role of the Wnt/β-catenin pathway in the cancer stemness of PGCCs. Critically, PGCCs with overexpressed cytoplasmic SIRT1 (SIRT1^NLSmt) showed increased CSC marker expression, chemoresistance, colony and spheroid formation abilities, and hyperactivation of the Wnt/β-catenin pathway, compared to PGCCs overexpressing the nuclear-predominant wild-type SIRT1 (SIRT1^WT). Mechanistically, cytoplasmic retention of SIRT1 in PGCCs stabilizes β-catenin, facilitates its nuclear accumulation, and decreases its deacetylation of nuclear β-catenin through post-translational modification. Our findings establish that the cytoplasmic SIRT1/β-catenin axis contributes to PGCC stemness, elucidating a novel mechanism underlying chemoresistance. Therefore, targeting cytoplasmic SIRT1 represents a promising therapeutic strategy to overcome PGCC-mediated resistance in this lethal carcinoma.

Keywords: Cancer stem cell; Chemoresistance; Ovarian cancer; Polyploid giant cancer cells (PGCCs); Sirtuin1; β-catenin.