PDK1 promotes epithelial ovarian cancer progression by upregulating BGN.

Abstract

Pyruvate dehydrogenase kinase 1 (PDK1) is a new therapeutic target that is dysregulated in multiple tumors. This study aims to explore the potential role and regulatory mechanism of PDK1 in epithelial ovarian cancer (EOC). We detect PDK1 expression in EOC tissues and cells using qRT-PCR and western blot analysis, and the effects of PDK1 on EOC cell malignant behaviors are explored. RNA sequencing analyses are performed to explore the differentially expressed genes in PDK1-silenced EOC cells. Furthermore, tumor-bearing mouse models are established to assess the impacts of PDK1 and BGN on EOC tumor growth and metastasis in vivo. The results show that PDK1 is upregulated in EOC tissues and cell lines. Biglycan (BGN) is downregulated in PDK1-silenced EOC cells, and its expression is positively correlated with PDK1 levels in EOC tissues. PDK1 depletion inhibits EOC cell proliferation, migration and invasion. Mechanistically, PDK1 and BGN are colocalized in the cytoplasm of EOC cells and interact with each other. PDK1 positively regulates BGN expression by enhancing BGN mRNA stability. BGN overexpression partially reverses the anti-tumor effects of PDK1 depletion on EOC cell malignant behaviors. PDK1 has also been revealed to upregulate BGN to activate the NF-κB oncogenic pathway in EOC cells. Additionally, PDK1 accelerates tumor growth and metastasis by modulating BGN expression. In conclusion, PDK1 functions as an oncogene, facilitating EOC progression by upregulating BGN and activating the NF-κB pathway. These findings may provide valuable biomarkers for the diagnosis and treatment of EOC.