Role of JMJD2B in colon cancer cell survival under glucose-deprived conditions and the underlying mechanisms

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.

KDM4B facilitates colorectal cancer growth and glucose metabolism by stimulating TRAF6-mediated AKT activation

“…The result is consisted with the previous study. In LN Fu et al work, they reported that knockdown of KDM4B could transcriptionally inhibit GLUT1 expression through increasing H3K9 tri-methylation levels on GLUT1 promoter [37]. In our study, we present a novel mechanism which KDM4B participate in glucose metabolism by the regulation of GLUT1.…”

Advances in histone demethylase KDM4 as cancer therapeutic targets

“…Recently, it was reported that KDM4B contributes to the mitigation of metastatic stress in CRC cells. KDM4B is upregulated via ERK phosphorylation (p‐ERK) during glucose deprivation in CRC cells . Glucose deprivation increases the interaction between KDM4B and p‐ERK, resulting in increased KDM4B phosphorylation and stability.…”

“…KDM4B is upregulated via ERK phosphorylation (p-ERK) during glucose deprivation in CRC cells. 98 Glucose deprivation increases the interaction between KDM4B and p-ERK, resulting in increased KDM4B phosphorylation and stability. The knockdown of KDM4B significantly decreases CRC cell viability and reduces glucose uptake and lactate production by downregulating GLUT1 expression.…”

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

“…Glucose transporter 1 (GLUT1), one of the major components regulating glucose homeostasis, 138 can be activated by p-ERK/KDM4B-mediated removal of the repressive H3K9me3 mark, thus contributing to glucose uptake in colon cancer cells under glucose deprivation conditions. 139 KMT2D inhibition mediates the loss of H3K4me3 in metabolic pathway genes, which results in alterations in aerobic glycolysis and lipid levels via GLUT3-mediated processes. 140 As GLUT3 exhibits a high affinity for glucose, thus ensuring efficient glucose uptake into cancer cells, 141 this process induces aerobic glycolysis and increases the levels of lipids, such as docosadienoic acid, docosatrienoic acid, and docosatetraenoic acid, which harbors oncogenic properties in PC cells.…”