MiR-422a regulates cellular metabolism and malignancy by targeting pyruvate dehydrogenase kinase 2 in gastric cancer

Zhongyuan He,Zekuan Xu,Qing Li,Zheng Li,Lu Zhang,Zhipeng Xu,Jianghao Xu,Hao Xu,Xuan Zhang,Kai Yin,Weizhi Wang,Lu Wang,Diancai Zhang,Xiaoxu Huang,Bowen Li,Lei Zhang,Guangli Sun

doi:10.1038/s41419-018-0564-3

Abstract

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Here, we showed that microRNA-422a (miR-422a) expression was dramatically downregulated in gastric cancer (GC) samples and cell lines compared with normal controls, and that its expression level was inversely related to tumor size and depth of infiltration. Functional studies revealed that the overexpression of miR-422a in GC tumor cells suppressed cell proliferation and migration, and drove a metabolic shift from aerobic glycolysis to oxidative phosphorylation. Mechanistic analysis suggested that miR-422a repressed pyruvate dehydrogenase kinase 2 (PDK2) to restore activity of the pyruvate dehydrogenase (PDH), the gatekeeping enzyme that catalyzes the decarboxylation of pyruvate to produce acetyl-CoA. Importantly, we further demonstrated that the mir-422a–PDK2 axis also influenced another metabolic pathway, de novo lipogenesis in cancer cells, and that it subsequently affected reactive oxygen species (ROS) and RB phosphorylation levels, ultimately resulting in cell cycle arrest in G1 phase. Our findings show that the miR-422a–PDK2 axis is an important mediator in metabolic reprogramming and a promising therapeutic target for antitumor treatment.

Highlights

Increasing evidence indicates that dysregulation of microRNAs plays a crucial role in human malignancies
The tumorigenesis and progression of gastric cancer (GC) are ing to the 3′-untranslated region (UTR) of target mRNAs, affected by multiple events through which cells undergo a resulting in their degradation or translational suppression
We showed that miR-422a acts as an effective suppressor of the Warburg effect by targeting pyruvate dehydrogenase kinase 2 (PDK2)

Summary

Introduction

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Functional studies revealed that the overexpression of miR-422a in GC tumor cells suppressed cell proliferation and migration, and drove a metabolic shift from aerobic glycolysis to oxidative phosphorylation. We further demonstrated that the mir-422a–PDK2 axis influenced another metabolic pathway, de novo lipogenesis in cancer cells, and that it subsequently affected reactive oxygen species (ROS) and RB phosphorylation levels, resulting in cell cycle arrest in G1 phase. In addition to aerobic glycolysis, cancer cells display abnormalities in other metabolic processes, including oxidative phosphorylation, glutaminolysis and lipogenesis[15,16,17].

Methods

Results

Conclusion