HKDC1 promotes metastasis, lipid metabolism and immune escape by interacting with G6PC/G6PC2 in ovarian cancer

Abstract

HKDC1 plays a critical role in tumor progression. However, its functional role in ovarian cancer (OC) metastasis, lipid metabolism, and immune escape remains incompletely understood. HKDC1 was knocked down and overexpressed in OC cells to investigate its effects and underlying mechanisms on metastasis, lipid metabolism, and immune evasion. Finally, an OC mouse model was established to validate the in vitro results. HKDC1 was found to be highly expressed in OC cell lines. Overexpression of HKDC1 promoted proliferation, migration, and invasion of OC cells. Additionally, HKDC1 upregulated levels of intracellular free fatty acids, triglycerides, phospholipids, and cholesterol, as well as neutral lipids content. HKDC1 enhanced fatty acid synthesis by upregulating the expression of ACC1, FASN, and SCD1. HKDC1 also promoted cholesterol biosynthesis by upregulating HMGCS1 and HMGCR expression. Knockdown of HKDC1 exerted opposite functional effects. Furthermore, HKDC1 upregulated PD-L1 expression, leading to increased immune suppression, manifested by inhibition of T cell proliferation, IFN-γ, GZMB, and perforin expression, and elevated PD-1 levels. Mechanistically, HKDC1 interacted with glucose-6-phosphatase catalytic subunit 1 (G6PC)/G6PC2 to exert its biological functions. These findings were further confirmed in the in vivo OC mouse model. HKDC1 promotes metastasis, lipid metabolism and immune escape by interacting with G6PC/G6PC2 in OC.