Abstract
Metabolic stress is a common phenomenon in solid tumors. Compensatory mechanisms to overcome metabolic stress (glucose deprivation) are vital to tumor cell survival. The histone demethylase Jumonji domain-containing protein 2B (JMJD2B) is vital for the growth and progression of various cancers. However, the role of JMJD2B during glucose deprivation remains unclear. Our aim was to examine the function of JMJD2B in glucose-deprived colon cancer cells and the involvement of extracellular signal-regulated kinase (ERK) and glucose transporter 1 (GLUT1). Our study demonstrated that JMJD2B expression was upregulated via ERK phosphorylation during glucose deprivation. Further, the cell viability assay showed that the effect of p-ERK on the viability of colon cancer cells was at least partly dependent on JMJD2B expression. Glucose deprivation increased interaction between JMJD2B and p-ERK, as demonstrated by the co-immunoprecipitation and fluorescence assays. Glucose deprivation also resulted in phosphorylation of JMJD2B by p-ERK, as shown by the immunoprecipitation assay and western blotting analysis. In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. We found that knockdown of JMJD2B significantly impaired colon cancer cell viability, which is accompanied by a significant reduction in glucose uptake and lactate production. Furthermore, knockdown of JMJD2B after glucose deprivation caused decreased level of GLUT1 through increasing H3K9 tri-methylation levels on its promoter, demonstrated by chromatin immunoprecipitation assay. Moreover, targeting JMJD2B in xenograft tumors also decreased the GLUT1 level. Finally, a positive correlation was observed between p-ERK, JMJD2B and GLUT1 expression in 85 human colon cancer tissue specimens. These results indicated that p-ERK-mediated phosphorylation and stabilization of JMJD2B during glucose deprivation contributes to its role in glucose uptake and cell viability, which may be modulated through epigenetically upregulation of GLUT1.
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Acknowledgements
This project was supported by the National Key Technology R&D Program (No. 2014BAI09B05), the National Natural Science Foundation of China (No. 81572303 to CYX, No. 81302085 to GQY and No. 81530072 to FJY), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (No. 20152210) & Program of Shanghai Academic/Technology Research Leader (No. 15XD1502600).
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Fu, LN., Wang, YQ., Tan, J. et al. Role of JMJD2B in colon cancer cell survival under glucose-deprived conditions and the underlying mechanisms. Oncogene 37, 389–402 (2018). https://doi.org/10.1038/onc.2017.345
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DOI: https://doi.org/10.1038/onc.2017.345
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