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ZDHHC8-mediated β-catenin palmitoylation promotes WNT signaling activation and drives cisplatin resistance in osteosarcoma

ABSTRACT: Chemoresistance remains a major challenge in osteosarcoma therapy, severely limiting the efficacy of cisplatin-based chemotherapy. Here, we identify the palmitoyltransferase ZDHHC8 as a critical determinant of cisplatin resistance and uncover a lipid modification–dependent mechanism that stabilizes β-catenin and sustains WNT signaling. ZDHHC8 expression was markedly upregulated in chemoresistant osteosarcoma tissues, and its knockdown significantly enhanced cisplatin-induced apoptosis both in vitro and in vivo. Transcriptomic profiling and functional assays revealed that ZDHHC8 depletion suppressed WNT/β-catenin signaling and diminished cancer stem cell–like properties. Mechanistically, ZDHHC8 directly interacted with β-catenin and catalyzed its C381-specific palmitoylation, which prevented proteasomal degradation and maintained protein stability. Mutation of C381 abolished β-catenin palmitoylation, resulting in reduced WNT activity and impaired stemness maintenance. Conversely, ZDHHC8 overexpression stabilized β-catenin and conferred cisplatin resistance. Collectively, our findings reveal a previously unrecognized ZDHHC8–β-catenin palmitoylation axis that governs WNT pathway activation and osteosarcoma chemoresistance. Targeting ZDHHC8 or disrupting β-catenin palmitoylation offers a promising therapeutic strategy to overcome drug resistance and improve osteosarcoma outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317900 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Increasing evidence has shown that chemoresistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long noncoding RNAs (lncRNAs) play pivotal roles in tumour metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin resistance induced EMT and metastasis are not well understood. In this study, a Chemotherapy Induced Long non-coding RNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells.Upregulation of CILA1 promotes EMT, invasiveness and chemoresistance in TSCC cells, whereas the inhibition of CILA1 expression induces MET and chemosensitivity and inhibis the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ β-catenin signalling pathway.High CILA1 expression levels and low levesl of phosphorylated β-catenin were closely associated with cisplatin-resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for Increasing evidence has shown that chemoresistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long noncoding RNAs (lncRNAs) play pivotal roles in tumour metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin resistance induced EMT and metastasis are not well understood. In this study, a Chemotherapy Induced Long non-coding RNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells.Upregulation of CILA1 promotes EMT, invasiveness and chemoresistance in TSCC cells, whereas the inhibition of CILA1 expression induces MET and chemosensitivity and inhibis the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ β-catenin signalling pathway.High CILA1 expression levels and low levesl of phosphorylated β-catenin were closely associated with cisplatin-resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for the chemosensitivity of TSCC tumours and a therapeutic target for TSCC treatment.

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ZDHHC8-mediated β-catenin palmitoylation promotes WNT signaling activation and drives cisplatin resistance in osteosarcoma

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