GTPBP4 promotes hepatocellular carcinoma progression and metastasis via the PKM2 dependent glucose metabolism
Qiang Zhou,
Yirui Yin,
Mincheng Yu,
Dongmei Gao,
Jialei Sun,
Zhangfu Yang,
Jialei Weng,
Wanyong Chen,
Manar Atyah,
Yinghao Shen,
Qinghai Ye,
Chia-Wei Li,
Mien-Chie Hung,
Qiongzhu Dong,
Chenhao Zhou,
Ning Ren
Affiliations
Qiang Zhou
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Yirui Yin
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China; Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
Mincheng Yu
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Dongmei Gao
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Jialei Sun
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Zhangfu Yang
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Jialei Weng
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Wanyong Chen
Institute of Fudan Minhang Academic Health System (AHS), Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, China
Manar Atyah
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Yinghao Shen
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Qinghai Ye
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
Chia-Wei Li
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Mien-Chie Hung
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
Qiongzhu Dong
Institute of Fudan Minhang Academic Health System (AHS), Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, China; Corresponding author. Institute of Fudan Minhang Academic Health System (AHS), Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, 170 Xinsong Road, Shanghai, 201100, China.
Chenhao Zhou
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Corresponding author. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Ning Ren
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China; Institute of Fudan Minhang Academic Health System (AHS), Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, China; Corresponding author. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Guanosine triphosphate binding protein 4 (GTPBP4) is a key regulator of cell cycle progression and MAPK activation. However, how its biological properties intersect with cellular metabolism in hepatocellular carcinoma (HCC) development remains poorly unexplained. Here, high GTPBP4 expression is found to be significantly associated with worse clinical outcomes in patients with HCC. Moreover, GTPBP4 upregulation is paralleled by DNA promoter hypomethylation and regulated by DNMT3A, a DNA methyltransferase. Additionally, both gain- and loss-of-function studies demonstrate that GTPBP4 promotes HCC growth and metastasis in vitro and in vivo. Mechanically, GTPBP4 can induce dimeric pyruvate kinase M2 (PKM2) formation through protein sumoylation modification to promote aerobic glycolysis in HCC. Notably, active GTPBP4 facilitates SUMO1 protein activation by UBA2, and acts as a linker bridging activated SUMO1 protein and PKM2 protein to induce PKM2 sumoylation. Furthermore, SUMO-modified PKM2 relocates from the cytoplasm to the nucleus may also could contribute to HCC progression through activating epithelial-mesenchymal transition (EMT) and STAT3 signaling pathway. Shikonin, a PKM2-specific inhibitor, can attenuate PKM2 dependent HCC glycolytic reprogramming, growth and metastasis promoted by GTPBP4, which offers a promising therapeutic candidate for HCC patients. Our findings indicate that GTPBP4-PKM2 regulatory axis plays a vital role in promoting HCC proliferation as well as metastasis by aerobic glycolysis and offer a promising therapeutic target for HCC patients.
