Abstract
Tripartite motif-containing protein 35 (TRIM35) is a member of RBCC family, which has a highly conserved order consisting of a RING domain followed by one or two B-Box domains and then a coiled-coil domain. We previously identified TRIM35 as a novel tumor suppressor in human hepatocellular carcinoma (HCC). However, the molecular mechanism that TRIM35 uses to suppress tumorigenicity is largely unknown. Pyruvate kinase isoform M2 (PKM2) has been demonstrated to have a central role in metabolic reprogramming during cancer progression. Phosphorylation of PKM2 tyrosine residue 105 (Y105) regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth. In the present work, mass spectrometry analysis demonstrated an interaction between TRIM35 and PKM2. Co-IP experiments confirmed that TRIM35 interacts with PKM2 and that the coiled-coil domain is required for such an interaction. Furthermore, the coiled-coil domain mediates decreases in the Warburg effect and in the cell proliferation of HCC cells. In addition, TRIM35 suppresses the tumorigenicity of HCC cells through the blockade of PKM2 Y105 phosphorylation. Collectively, our data reveal a new function for TRIM35, which is to regulate the Warburg effect and tumorigenicity through interaction with PKM2 in HCC.
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Acknowledgements
We are grateful for Dr T Didier’s gifts of the pWPXL, psPAX2 and pMD2.G lentivirus plasmids. We thank Qunying Lei for discussions throughout this study. We thank Jianhua Zhu for use of the scintillation counter. We thank Feng Wang and Ping Zhang for technical assistance. This work was supported by grants from the National 973 Key Basic Research Program (2013CB910504), Shanghai Natural Science Fund for Youth Scholars (12ZR1449900), Shanghai Rising-Star Program (12QA1403100), Shanghai ‘Promising Youth Medical Worker’ Project (XYQ2011042), National Natural Science Foundation of China (81201538, 81125016, 81171942).
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Chen, Z., Wang, Z., Guo, W. et al. TRIM35 Interacts with pyruvate kinase isoform M2 to suppress the Warburg effect and tumorigenicity in hepatocellular carcinoma. Oncogene 34, 3946–3956 (2015). https://doi.org/10.1038/onc.2014.325
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DOI: https://doi.org/10.1038/onc.2014.325
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