PBRM1 knockdown is associated with NRF2‑dependent ALDOA upregulation and metabolic reprogramming in HCCC‑9810 intrahepatic cholangiocarcinoma cells

Polybromo-1 (PBRM1) is a chromatin-remodeling factor that is altered in intrahepatic cholangiocarcinoma (ICC).The present study examined the effects of PBRM1 knockdown on tumor-related phenotypes and glucose metabolism in HCCC-9810 ICC cells.The present study also evaluated the roles of aldolase, fructose-bisphosphate A (ALDOA) and nuclear factor erythroid 2-related factor 2 (NRF2).Publicly available ICC mutation data were analyzed descriptively.The present study evaluated HCCC-9810 cells following PBRM1 knockdown using proliferation, colony formation, wound-healing, Transwell, metabolic, reverse transcription-quantitative PCR, western blotting, apoptosis and mitochondrial membrane-potential assays.ALDOA and NRF2 perturbation experiments were used to examine their contribution to the PBRM1-knockdown phenotype.HCCC-9810-derived xenografts were used for in vivo assessment.PBRM1 knockdown increased proliferation, migration and invasion in HCCC-9810 cells and altered several glucose-metabolism readouts.ALDOA expression also increased following PBRM1 knockdown.ALDOA silencing attenuated several metabolic and survival-related changes.NRF2 overexpression increased ALDOA expression, whereas NRF2 knockdown reduced it.Co-silencing NRF2 attenuated the ALDOA increase associated with PBRM1 knockdown.In xenografts, PBRM1 knockdown was associated with greater tumor growth, higher ALDOA expression and a higher Ki67 signal.PBRM1 knockdown was associated with a tumor-promoting metabolic phenotype in HCCC-9810 cells, with ALDOA contributing to several metabolic and survival-related changes.NRF2 perturbation further supported an NRF2-dependent component of ALDOA regulation in this HCCC-9810 model; however, the upstream mechanism responsible for increased NRF2 after PBRM1 knockdown remains unresolved.These findings warrant validation in independent ICC models.