Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer

Zhan, Cheng; Shi, Ying‐Hong; Chen, Lu; Wang, Q.

doi:10.1111/dote.12023

Cited by 23 publications

(21 citation statements)

References 28 publications

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“…Previously it has been reported that PKM2 behaves as a poor prognostic factor in signet ring cell gastric cancer and esophageal squamous cell cancer [19,20]. These tumors types were not included in our study.…”

Section: Discussionmentioning

confidence: 99%

“…PKM2, but not PKM1, is translocated into nucleus after EGFR activation and binds beta-catenin to regulate gene transcription [16]. Elevated expression of PKM2 has been reported in many types of cancers including colon and breast cancers [17,18] and is associated with poor prognosis in signet ring cell gastric cancer and esophageal squamous cell cancer [19,20]. As such, efforts were made to identify small molecule inhibitors specifically targeting PKM2 for anticancer therapy [21].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…Therefore, these glycolytic enzymes may be regulated by tumorigenic factors or may regulate tumorigenesis in parallel. For one example, many glycolytic enzymes are highly correlated with tumor prognosis [5,12–28]; for another example, hypoxia inducible factor-1 (HIF-1) is one of the key regulators of many glycolytic enzymes and of the Warburg effect [13,21,29–35]. …”

Section: Discussionmentioning

confidence: 99%

Isoform Switch of Pyruvate Kinase M1 Indeed Occurs but Not to Pyruvate Kinase M2 in Human Tumorigenesis

Zhan

Wang

et al. 2015

PLoS ONE

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Muscle type of pyruvate kinase (PKM) is one of the key mediators of the Warburg effect and tumor metabolism. Due to alternative splicing, there are at least 12 known isoforms of the PKM gene, of which PKM1 and PKM2 are two major isoforms with only a 23 amino acid sequenced difference but quite different characteristics and functions. It was previously thought the isoform switch from PKM1 to PKM2 resulted in high PKM2 expression in tumors, providing a great advantage to tumor cells. However, this traditional view was challenged by two recent studies; one study claimed that this isoform switch does not occur during the Warburg effect; the other study asserted that the isoform switch is tissue-specific. Here, we re-analyzed the RNA sequencing data of 25 types of human tumors from The Cancer Genome Atlas Data Portal, and confirmed that PKM2 was the major isoform in the tumors and was highly elevated in addition to the entire PKM gene. We further demonstrated that the expression level of PKM1 significantly declined even though there was substantially increased expression of the entire PKM gene. The proportion of PKM1 in total transcript variants also significantly declined in tumors but the proportion of PKM2 did not change accordingly. Therefore, we conclude that the isoform switch of PKM1 does indeed occur, but it switches to other isoforms rather than PKM2. Considering the change in the expression levels of PKM1, PKM2 and the entire PKM gene, we propose that the upregulation of PKM2 is primarily due to elevated transcriptional levels of the entire PKM gene, instead of the isoform switch.

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“…Recent studies suggest that heightened expression of PKM2 is critical for the maintenance of cancer cell growth and is associated with a poor prognosis in some types of cancer1920. On the other hand, it was previously thought that PKM1 is expressed in normal differentiated tissues and that the switching of PKM expression from PKM1 to PKM2 occurs during cancer development1821.…”

mentioning

confidence: 99%

Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms

Taniguchi

Ito

Sugito

et al. 2015

Sci Rep

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The Warburg effect is a well-known feature of cancer cells. However, its' functional significance hasn't been elucidated yet. Pyruvate kinase muscle (PKM), which is a rate-limiting glycolytic enzyme, has 2 isoforms, PKM1 and PKM2. It has been reported that PKM2 is a tumor-specific isoform and promotes the Warburg effect. Also, it has been thought that tumor cells switch their PKM isoform from PKM1 to PKM2 during tumor development. Here, we showed that this switching machinery was induced only in limited cases, based on PKM expression in normal tissues, and that brain-specific microRNA (miR)-124 and muscle-specific miR-133b regulated this machinery by controlling PKM expression through targeting polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of the PKM gene. Also, we confirmed that the PKM2/PKM1 ratio was further elevated in other PKM2-dominant organs such as colon through the down-regulation of these PTB1-associated microRNAs during tumor development.

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Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer

Cited by 23 publications

References 28 publications

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

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

Isoform Switch of Pyruvate Kinase M1 Indeed Occurs but Not to Pyruvate Kinase M2 in Human Tumorigenesis

Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms

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