Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers

Shruti Desai,John N Weinstein,Minming Ding,Qi Zhao,Zhimin Lu,Kenna Shaw,W.K Alfred Yung,Bin Wang,Ming Tan,Jun Yao

doi:10.18632/oncotarget.1159

Abstract

The M2 isoform of pyruvate kinase (PKM2) plays an important role in aerobic glycolysis and is a mediator of the Warburg effect in tumors. It was previously thought that tumor cells switch expression of PKM from normal tissue-expressed PKM1 to tumor-specific PKM2 via an alternative splicing mechanism. This view was challenged by a recent report demonstrating that PKM2 is already the major PKM isoform expressed in many differentiated normal tissues. Here, through analyses on sixteen tumor types using the cancer genome atlas RNA-Seq and exon array datasets, we confirmed that isoform switch from PKM1 to PKM2 occurred in glioblastomas but not in other tumor types examined. Despite lacking of isoform switches, PKM2 expression was found to be increased in all cancer types examined, and correlated strongly to poor prognosis in head and neck cancers. We further demonstrated that elevated PKM2 expression correlated well with the hypomethylation status of intron 1 of the PKM gene in multiple cancer types, suggesting epigenetic regulation by DNA methylation as a major mechanism in controlling PKM transcription in tumors. Our study suggests that isoform switch of PKM1 to PKM2 in cancers is tissue-specific and targeting PKM2 activity in tumors remains a promising approach for clinical intervention of multiple cancer types.

Highlights

Aerobic glycolysis, wherein cells take up more glucose and produce large amounts of lactate in presence of oxygen, is a key feature of many cancer cells
Among all tumors having normal controls we found PKM2 was expressed as the major isoform in both tumor and normal tissues
This revealed that PKM2/PKM1 ratio increased in majority of the tumors compared to autologous normal samples, suggesting there might be a further shift of expression toward the PKM2 isoform in tumors

Summary

Introduction

Wherein cells take up more glucose and produce large amounts of lactate in presence of oxygen, is a key feature of many cancer cells. This altered glucose metabolism is known as Warburg effect [1]. PKM2, the M2 isoform of the glycolytic enzyme pyruvate kinase, has been shown to promote Warburg effect and tumorigenesis by functioning as a HIF1 co-activator [8,9,10,11]. Increased activity of PKM2 in human cancers is reported to regulate amino acid homeostasis and affect protein expression in thyroid cancer [12]

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Results

Conclusion