Clinical and translational medicine
ATF6-mediated GTPase RHOQ promotes liver cancer progression via enhancing aerobic glycolysis through PAK1 phosphorylation
By Zheng Y, Li W, Guo Y and 3 others.
Abstract
Background
Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumours worldwide, accounting for approximately 90% of primary liver cancer cases, with the highest incidence observed in Asia. Activating Transcription Factor 6 (ATF6) is an endoplasmic reticulum stress-responsive transcription factor. Our previous studies have demonstrated that ATF6 contributes to HCC tumourigenesis and progression through signalling pathways such as ATF6-CTH-Keap1-mTORC1 and ATF6-PPM1H-RPS6KB1.
Methods
RNA sequencing identified ATF6 transcriptional targets, with Ras homolog family member Q (RHOQ) validation via chromatin immunoprecipitation and electrophoretic mobility shift assay. RHOQ expression and clinical significance were analysed in HCC cohorts. Functional assays assessed proliferation, migration, invasion and epithelial-mesenchymal transition (EMT). Tumour growth was evaluated in orthotopic (NOG mice) and subcutaneous (nude mice) models. Mechanistic analyses were performed to characterise RHOQ-mediated regulation of p21-activated kinase 1 (PAK1) signalling and metabolic remodelling. Furthermore, therapeutic synergy between PAK1 inhibitor IPA-3 and Glypican-3 (GPC3)-CAR T cells was tested.