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

Abstract

Background: Histone lysine demethylase 4B (KDM4B) has been implicated in various pathological processes and human diseases. Glucose metabolism is the main pattern of energy supply in cells and its dysfunction is closely related to tumorigenesis. Recent study shows that KDM4B protects against obesity and metabolic dysfunction. We realized the significant role of KDM4B in metabolism. However, the role of KDM4B in glucose metabolism remains unclear. Here, we sought to delineate the role and mechanism of KDM4B in glucose metabolism in colorectal cancer (CRC). Methods: We first analyzed the role of KDM4B in glucose uptake and CRC growth. We then investigated the consequences of KDM4B inhibition on the expression of GLUT1 and AKT signaling, also explored the underlying mechanism. Finally, we detected the mechanism in vivo and assessed the potential correlation between the expression of KDM4B and CRC prognosis. Results: We found that KDM4B promoted glucose uptake and ATP production by regulating the expression of GLUT1 via the AKT signaling pathway. KDM4B could interact with TRAF6 and promote TRAF6-mediated ubiquitination of AKT for AKT activation. Furthermore, we demonstrated that KDM4B was overexpressed in CRC specimens and high level of KDM4B was associated with a poor survival rate in CRC patients. Conclusions: These findings reveal that KDM4B plays an important role in promoting CRC progression by enhancing glucose metabolism.

MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis

“…While our data presented that IFN-γ stimulated KDM4B expression to induce PD-L1 and Galenctin-9 expression in CRC cells. The oncogenic roles of KDM4B have been widely probed in different cancers, including ovarian cancer ( Wilson et al, 2017 ), gastric cancer ( Zhao et al, 2013 ), as well as CRC ( Li et al, 2020 ). Moreover, histone demethylase KDM4B synergizes H3K4/H3K9 methylation and enhances hormonally responsive breast cancer ( Shi et al, 2011 ).…”

The role of ubiquitination and deubiquitination in cancer metabolism

“…SETDB1 catalyzed methylation of AKT enhances its K63-linked ubiquitination and activation [83]. After interaction with KDM4B, TRAF6 promotes its ubiquitination of AKT in colorectal cancer, facilitating glucose metabolism and tumor growth [84]. DUB CYLD, OTUD5 and USP1 can reverse K63-linked polyubiquitination of AKT and inhibit its activation [85][86][87].…”

CircAGFG1 drives metastasis and stemness in colorectal cancer by modulating YY1/CTNNB1

“…Evidence showed the participation of various signaling pathways in CRC progression, such as Wnt/β-catenin pathway 24 , AKT pathway 25 , and Notch pathway 26 . To explore the downstream signaling by which circAGFG1 could exert its function, Wnt/β-catenin pathway activator (LiCl), AKT pathway activator (SC79) and Notch pathway activator (Jagged1) were used for rescue assays.…”