ATF6‐mediated GTPase RHOQ promotes liver cancer progression via enhancing aerobic glycolysis through PAK1 phosphorylation
- 1Chinese Academy of Medical Sciences & Peking Union Medical College
- 2the Affiliated Hospital of Qingdao University
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. Results We identified RHOQ as a direct transcriptional target of ATF6. Clinically, elevated RHOQ expression correlated with poorer progression‐free survival (PFS) in patients with HCC. Functionally, RHOQ promoted the proliferation and metastasis of liver tumour cells. Correspondingly, RHOQ knockdown markedly suppressed tumour growth in xenograft models, with consistent results observed in a hydrodynamic tail vein injection(HTVi) model. Mechanistic investigations revealed that RHOQ directly bound to PAK1, promoted its phosphorylation and activation and thereby drove aerobic glycolysis in liver tumour cells. Furthermore, combined treatment with the PAK1‐specific inhibitor IPA‐3 and GPC3‐targeted CAR T‐cell therapy produced a significant synergistic anti‐tumour effect. Conclusion In summary, this study systematically delineated the importance of the ATF6–RHOQ–PAK1 signalling cascade in driving liver cancer progression and provided a rationale for the design of targeted combination therapies. Highlights RHOQ is a novel direct transcriptional target of ATF6 in HCC. High RHOQ expression is associated with unfavourable clinicopathological features and poorer PFS. RHOQ drives HCC progression via PAK1 activation and aerobic glycolysis. Combining the PAK1‐specific inhibitor IPA‐3 with GPC3‐targeted CAR T‐cell therapy produces a potent synergistic anti‐tumour effect.
Related
- SEC31A promotes gastric cancer progression by inducing the PI3K/AKT/mTOR pathway and enhancing the CCL5-mediated M2 polarization and recruitment of tumor-associated macrophages
- Oncogenic CLDN1 promotes thyroid cancer progression through TAp63-mediated glycolytic switching
- Lysosomal Dysfunction-Mediated IgG Accumulation Promotes Endothelial Senescence and Lesion Progression in Cerebral Cavernous Malformations
- TM9SF1 Promotes YAP‐Mediated EMT of Alveolar Epithelial Cells in VILI by Enhancing Autophagic Degradation of CLDN18
- Glycolysis-enhancing α1-adrenergic antagonists have therapeutic potential in Alzheimer’s disease
BibTeX
@article{zheng2026atf6mediated,
title = {{ATF6‐mediated GTPase RHOQ promotes liver cancer progression via enhancing aerobic glycolysis through PAK1 phosphorylation}},
author = {Yuange Zheng and Wei Li and Yuxin Guo and Xilin Zhu and Ying Liu and Xiaopan Wu},
journal = {Clinical and translational medicine},
year = {2026},
month = oct,
doi = {10.1002/ctm2.70871},
url = {https://europepmc.org/article/PMC/PMC13670142},
note = {CC BY},
}
RIS
TY - JOUR
TI - ATF6‐mediated GTPase RHOQ promotes liver cancer progression via enhancing aerobic glycolysis through PAK1 phosphorylation
AU - Yuange Zheng
AU - Wei Li
AU - Yuxin Guo
AU - Xilin Zhu
AU - Ying Liu
AU - Xiaopan Wu
PY - 2026
DA - 2026/10/01
JO - Clinical and translational medicine
DO - 10.1002/ctm2.70871
UR - https://europepmc.org/article/PMC/PMC13670142
AB - 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. Results We identified RHOQ as a direct transcriptional target of ATF6. Clinically, elevated RHOQ expression correlated with poorer progression‐free survival (PFS) in patients with HCC. Functionally, RHOQ promoted the proliferation and metastasis of liver tumour cells. Correspondingly, RHOQ knockdown markedly suppressed tumour growth in xenograft models, with consistent results observed in a hydrodynamic tail vein injection(HTVi) model. Mechanistic investigations revealed that RHOQ directly bound to PAK1, promoted its phosphorylation and activation and thereby drove aerobic glycolysis in liver tumour cells. Furthermore, combined treatment with the PAK1‐specific inhibitor IPA‐3 and GPC3‐targeted CAR T‐cell therapy produced a significant synergistic anti‐tumour effect. Conclusion In summary, this study systematically delineated the importance of the ATF6–RHOQ–PAK1 signalling cascade in driving liver cancer progression and provided a rationale for the design of targeted combination therapies. Highlights RHOQ is a novel direct transcriptional target of ATF6 in HCC. High RHOQ expression is associated with unfavourable clinicopathological features and poorer PFS. RHOQ drives HCC progression via PAK1 activation and aerobic glycolysis. Combining the PAK1‐specific inhibitor IPA‐3 with GPC3‐targeted CAR T‐cell therapy produces a potent synergistic anti‐tumour effect.
SN - 2001-1326
ER -