FOXM1D potentiates PKM2-mediated tumor glycolysis and angiogenesis.

Wei Zhang,Jianfeng Chen,Yiping Wang,Danlei Zhou,Qi Wang,Peipei Ding,Xin Zhang,Jiong Wu,Pingzhao Zhang,Weiguo Hu,Ling Li,Luying Li,Wenyu Wen,Qun‐Ying Lei,Sheng Huang,Xinyue Lv

doi:10.1002/1878-0261.12879

Wei Zhang, Jianfeng Chen + Show 14 more

Open Access

https://doi.org/10.1002/1878-0261.12879

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Journal: Molecular oncology	Publication Date: Apr 2, 2021
Citations: 33	License type: CC BY 4.0

Affiliation: Fudan University Shanghai Cancer Center

Abstract

Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late-stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2-mediated glycolysis and angiogenesis through multiple protein-protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF-κB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF-κB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.

Highlights

Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role
We found that FOXM1D interplays with multiple proteins including PKM2, importin 4, NF-κB, and VPS11, it promoting aerobic glycolysis through assembly a heterooctamer with PKM2, which enhances angiogenesis by increasing the expression and release of VEGF
Using Co-IP and ICC assays, we demonstrated that importin 4 bound to FOXM1A/D but not to FOXM1B/C (Fig. 6c-d), indicating that FOXM1B/C employed a different approach to inducing nuclear translocation of PKM2 and NF-κB from FOXM1A/D

Summary

Introduction

Especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. PKM2 normally presents in either a homotetramer form that allows for the highly effective conversion of glucose to lactate, acting as a metabolite kinase, or a low activity homodimer form that uses PEP as a phosphate donor to phosphorylate tyrosine residues, acting as a signal transducer and activator of transcription [10, 13] Upon upstream stimulus, such as epidermal growth factor (EGF) or interleukin-3, PKM2 translocates into the nucleus to play a non-metabolic role as a histone kinase and/or a transcriptional coactivator, promoting the Warburg effect and cell cycle progression via cyclin D1 and β-catenin [14,15,16,17,18]

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