Cancer cells reprogram their energy metabolic system from the mitochondrial oxidative phosphorylation (OXPHOS) pathway to a glucose-dependent aerobic glycolysis pathway. This metabolic reprogramming phenomenon is known as the Warburg effect, a significant hallmark of cancer. However, the detailed mechanisms underlying this event or triggering this reprogramming remain largely unclear. Here, we found that histone H2B monoubiquitination (H2Bub1) negatively regulates the Warburg effect and tumorigenesis in human lung cancer cells (H1299 and A549 cell lines) likely through controlling the expression of multiple mitochondrial respiratory genes, which are essential for OXPHOS. Moreover, our work also suggested that pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, can directly interact with H2B in vivo and in vitro and negatively regulate the level of H2Bub1. The inhibition of cell proliferation and nude mice xenograft of human lung cancer cells induced by PKM2 knockdown can be partially rescued through lowering H2Bub1 levels, which indicates that the oncogenic function of PKM2 is achieved, at least partially, through the control of H2Bub1. Furthermore, PKM2 and H2Bub1 levels are negatively correlated in cancer specimens. Therefore, these findings not only provide a novel mechanism triggering the Warburg effect that is mediated through an epigenetic pathway (H2Bub1) but also reveal a novel metabolic regulator (PKM2) for the epigenetic mark H2Bub1. Thus, the PKM2-H2Bub1 axis may become a promising cancer therapeutic target.
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We thank Dr Weiwei Yang from the Shanghai Institute of Biochemistry and Cell Biology (SIBS, CAS) for kindly providing the PKM2-related plasmids. This work was supported by the National Key Research and Development Program of China (Grant No.: 2017YFA0103301 and 2016YFA0100403), the 973 program of the Ministry of Science and Technology of China (Grant No.: 2015CB856204, 2015CB964802), the National Natural Science Foundation of China (Grant No.: 91419304, 81773009, 81972650, 31330043, and 31271534), the Fundamental Research Funds for the Central Universities (Xi’an Jiao Tong University, Grant No.: 2017qngz13), and the China Postdoctoral Science Foundation (Grant No.: 2017M613149 and 2018T111038).
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Jing, Y., Cai, F., Zhang, L. et al. Epigenetic regulation of the Warburg effect by H2B monoubiquitination. Cell Death Differ (2019). https://doi.org/10.1038/s41418-019-0450-2