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.