Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers.
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.
Mitchell Cancer Institute, Departments of Cell Biology and Neuroscience, University of South Alabama, Mobile, USA.
Shruti
S
Desai
Division of Biostatistics, School of Public Health, The University of Texas - Houston Health Science Center, Houston, USA.
Minming
M
Ding
Department of Genetics, The University of Texas M. D. Anderson Cancer Center, The University of Texas - Houston Health Science Center, Houston, USA.
Bin
B
Wang
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, The University of Texas - Houston Health Science Center, Houston, USA.
Zhimin
Z
Lu
Ludwig Collaborative Laboratory, Department of Neurosurgery, Johns Hopkins University, 1550 Orleans Street, Baltimore, USA.
Qi
Q
Zhao
Department of TCGA Genome Data Analysis Center, The University of Texas M. D. Anderson Cancer Center, The University of Texas - Houston Health Science Center, Houston, USA.
Kenna
K
Shaw
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, The University of Texas - Houston Health Science Center, Houston, USA.
W K Alfred
WK
Yung
Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, The University of Texas - Houston Health Science Center, Houston, USA.
John N
JN
Weinstein
Mitchell Cancer Institute, Departments of Cell Biology and Neuroscience, University of South Alabama, Mobile, USA.
Ming
M
Tan
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, The University of Texas - Houston Health Science Center, Houston, USA.
Jun
J
Yao
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics; D016000:Cluster Analysis; D019175:DNA Methylation; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007438:Introns; D007527:Isoenzymes; D053208:Kaplan-Meier Estimate; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D007527:Isoenzymes; D011770:Pyruvate Kinase