KPNA2 promotes metabolic reprogramming in glioblastomas by regulation of c-myc

Abstract

BackgroundCancer cells maintain energy metabolism mainly by glycolysis, even under sufficient oxygen conditions. It gives cancer cells better growth advantages under complicated internal environment. KPNA2 is a novel oncogene that has received much attention in recent years, but the exact mechanisms of KPNA2 in tumorigenesis and progression are largely unknown. Especially its potential roles in the metabolic transformation of tumors still remain to be explored.MethodsThe expressions of KPNA2 in glioblastoma and normal human brain samples were analyzed by immunohistochemical analysis. The activities of key enzymes in glycolysis, the production of lactate acid and glucose uptake were investigated by colorimetry. GLUT-1 expression was measured by flow cytometry. CCK8 was used to examine the cell viability in vitro, and the xenograft models in nude mice were established to explore the roles of KPNA2 in vivo. In addition, Co-IP, subcellular fractionation, western blot, immunofluorescence and luciferase assay were used to investigate the internal connection between KPNA2, c-myc and E2F1.ResultsIn the present study, we found that KPNA2 was highly expressed in the glioma compared to the normal brain tissues. Level of KPNA2 was an independent predictor of prognosis in the glioma patients. Knockdown of KPNA2 in the glioblastoma cell lines U87 and U251 decreased deoxyglucose uptake, activities of the key glycolytic enzymes and lactate production. The level of oxidative phosphorylation (OXPHOS) was moderately decreased. Additioanlly, tumor proliferation and invasiveness were concomitantly downregulated. We have identified c-myc as a potential mediator of KPNA2. Aberrant expression of KPNA2 significantly changed the subcellular distribution of c-myc as well as its expression level. E2F1, another key cargo protein of KPNA2, was further identified to play a potential role in regulating the transcription of c-myc by KPNA2.ConclusionsOur findings suggested that KPNA2, a potential tumor oncogene, performs its function in part via regulating cellular metabolism through c-myc signaling axis. It would provide a possible explanation for Warburg effect and thus offer a new perspective to the roles of KPNA2 in gliomagenesis.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0861-9) contains supplementary material, which is available to authorized users.

Zika virus NS2A protein induces the degradation of KPNA2 (karyopherin subunit alpha 2) via chaperone-mediated autophagy

“…Each isoform of KPNAs has its preference for cargos. KPNA2 transports the POU domain transcription factor POU5F1/OCT4 (POU class 5 homeobox 1) [11], transcription factor MYC/c-Myc [12], E2F1 [13], the small GTPase RAC1 [14], the deoxynucleotidetriphosphate (dNTP) hydrolase SAMHD1 (sterile alpha motif and histidine/aspartic acid domain 1) [15], RELA/NF-κB p65 [16], NBN/NBS1 [17] and so on. However, KPNA2 inhibits the nuclear translocation of POU transcription factor POU3F1/OCT6 and POU3F2/BRN2 [18].…”

IL-10 Promotes Glioma Cell Growth and Invasion via Upregulation of KPNA2 In vitro

“…In view of a recent study showed that KPNA2 plays a crucial role in the metabolic reprogramming of glioma cells by mediating the nuclear transportation of c-Myc and E2F1 [30], we hypothesis that IL-10 may have an important role in regulating the metabolism of glioma cells, but further experiments are needed to prove it.…”

A nuclear transport-related gene signature combined with IDH and 1p/19q better predicts the prognosis of glioma patients

“…Gene signature panels based on NTRS should be developed, and real-world research (RWR) involving multiple centers should be performed in the future. Although all seven genes were signi cantly associated with survival in multiple datasets (TCGA, CGGA and Rembrandt) and several of the genes have been reported to be functional in gliomas [14][15][16], further experiments are needed to study the function and mechanism of these seven genes, which will be performed in the future.…”