Latent Membrane Protein 1 Promotes Tumorigenesis Through Upregulation of PGC1\u03b2 Signaling Pathway

Jia Feng,Xiaodong Huang,Qi Chen,Weiguo Xie,Paul Yao,Hongyu Zhang,Ping Zhang

doi:10.1007/s12015-020-10112-8

Jia Feng, Xiaodong Huang + Show 5 more

Open Access

https://doi.org/10.1007/s12015-020-10112-8

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Abstract

Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with poor prognosis. In this study, we aimed to investigate the potential mechanism of latent membrane protein 1 (LMP1)-mediated tumorigenesis and provide a novel therapeutic strategy for targeting the EBV DNA genome. We found that LMP1 upregulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1β (PGC1β) through activation of nuclear factor-κB (NF-κB). Furthermore, the activated PGC1β upregulated the expression of 8-oxoguanine DNA glycosylase (OGG1) through the coactivation of nuclear respiratory factor 1 (NRF1) and GA-binding protein α (GABPα), preventing reactive oxygen species (ROS)-mediated base incision in the EBV genome and favoring its survival. Interruption of hexokinase domain component 1 (HKDC1) by either shRNA or Tf-D-HKC8 peptide suppressed the interaction of HKDC1 with voltage-dependent anion channel 1 (VDAC1), triggering mitochondrial dysfunction and excessive generation of ROS, thus resulting in EBV suppression through ROS-mediated DNA damage. Suppression of the EBV genome inhibited the expression of the LMP1/PGC1β/HKDC1/OGG1 signaling pathway, forming a positive feed forward loop for the generation of ROS, hence inhibiting the EBV genome and subsequent EBV-associated tumor development. We concluded that LMP1 triggers EBV-associated tumorigenesis through activation of the PGC1β pathway. This study provided a novel therapeutic strategy for the treatment of EBV-associated tumors by targeting HKDC1.Graphical

Highlights

Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with a high prevalence in most Asian populations [1,2,3]
Our results showed that the latent membrane protein 1 (LMP1) mRNA was not expressed in healthy peripheral blood mononuclear cells (PBMCs), whereas significant levels of expression were observed in other NKTCL cell lines
We found that the mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC1β) and 8-oxoguanine DNA glycosylase 1 (OGG1) were increased to 178% and 164% in HANK1 cells compared with PMBC cells

Summary

Introduction

Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with a high prevalence in most Asian populations [1,2,3]. The latent membrane protein 1 (LMP1) encoded by EBV is known to be a direct target gene of Epstein–Barr virus nuclear antigen 2 (EBNA2). LMP1 has 6 hydrophobic membrane-spanning domains and a 200amino acid cytoplasmic carboxyl terminus, which is comprised of 2 domains, named transformation effector sites 1 and 2 (TES1 and TES2), respectively. These 2 domains are known to be responsible for the transformation of B-cells and the activation of the nuclear factor-κB (NF-κB) [14], which

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