Discovery of Functional Alternatively Spliced &lt;i&gt;PKM&lt;/i&gt; Transcripts in Human Cancers

Xiangyu Li,Jens Nielsen,David Kotol,Per Oksvold,Björn Forsström,Muhammad Arif,Chunxia Gao,Linnéa Strandberg,Andreas Hober,Yusuke Sato,Cheng Zhang,Seishi Ogawa,Åsa Sivertsson,Haruki Kume,Mathias Uhlén ,Hasan Türkez ,Woonghee Kim ,Morten Grøtli ,Jan Borén ,Adil Mardinoğlu

doi:10.2139/ssrn.3713513

Abstract

The association of pyruvate kinase muscle type (PKM) with survival of cancer patients is controversial. Here, we focus on different transcripts of PKM and investigate the association between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcripts encoding PKM2, and three previously unstudied transcripts, namely ENS0389093, ENS0568883 and ENS0561609, exhibited opposite prognostic indications in different cancers. Moreover, we validate the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we reveal that ENS0389093 and ENS0568883 possess pyruvate kinase enzymatic activity and could have functional roles in metabolism, cell invasion and hypoxia response in cancer cells. Our study provided a potential explanation to the controversial prognostic indication of PKM, and could invoke future studies focusing on revealing the biological and oncological role of these alternative spliced variants of PKM.

Highlights

Pyruvate kinase muscle type (PKM) is the most-studied isoform of pyruvate kinase and catalyzes the final step in glycolysis [1]
We investigated the enriched gene ontology (GO) terms associated with PKM2
We found that the protein product of PKM-609 is shorter than PKM2, missing amino acid residues 486-531aa from PKM2 which is a part of the C-domain participating in the formation of tetramer [44]

Summary

Introduction

Pyruvate kinase muscle type (PKM) is the most-studied isoform of pyruvate kinase and catalyzes the final step in glycolysis [1]. It is one of the key mediators of the Warburg effect and plays a pivotal role in controlling tumor metabolism. It has been reported that the mRNA and protein expression of PKM is strongly associated with the survival of cancer patients, but the direction of the correlation was contradictory since both activation and inhibition of this enzyme have been suggested for effective treatment of the cancer patients [2]. Tetrameric PKM2 exhibits high catalytic activity, which is associated with ATP synthesis and catabolic metabolism [9], while dimeric

Methods

Results

Conclusion