Discovery of functional alternatively spliced PKM transcripts in human cancers

TY - JOUR

T1 - Discovery of functional alternatively spliced PKM transcripts in human cancers

AU - Li, Xiangyu

AU - Kim, Woonghee

AU - Arif, Muhammad

AU - Gao, Chunxia

AU - Hober, Andreas

AU - Kotol, David

AU - Strandberg, Linnéa

AU - Forsström, Björn

AU - Sivertsson, Åsa

AU - Oksvold, Per

AU - Turkez, Hasan

AU - Grøtli, Morten

AU - Sato, Yusuke

AU - Kume, Haruki

AU - Ogawa, Seishi

AU - Boren, Jan

AU - Nielsen, Jens

AU - Uhlen, Mathias

AU - Zhang, Cheng

AU - Mardinoglu, Adil

N1 - Funding Information: Funding: This research was funded by Knut och Alice Wallenbergs Stiftelse grant number CJDB 72110. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1/2

Y1 - 2021/1/2

N2 - Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of PKM expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of PKM transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of PKM and investigated the associations 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 ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may 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 roles of these alternative spliced variants of PKM.

AB - Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of PKM expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of PKM transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of PKM and investigated the associations 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 ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may 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 roles of these alternative spliced variants of PKM.

KW - Alternative splicing

KW - Cancer

KW - PKM

KW - Transcriptomics

UR - http://www.scopus.com/inward/record.url?scp=85100137584&partnerID=8YFLogxK

U2 - 10.3390/cancers13020348

DO - 10.3390/cancers13020348

M3 - Article

AN - SCOPUS:85100137584

SN - 2072-6694

VL - 13

SP - 1

EP - 23

JO - Cancers

JF - Cancers

IS - 2

M1 - 348

ER -