Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers
Journal article, 2021

Simple Summary Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and is a mediator of the Warburg effect in tumors. The association of PKM with survival of cancer patients is controversial. In this study, we investigated the associations of the alternatively spliced transcripts of PKM with cancer patients' survival outcomes and explained the conflicts in previous studies. We discovered three poorly studied alternatively spliced PKM transcripts that exhibited opposite prognostic indications in different human cancers based on integrative systems analysis. We also detected their protein products and explored their potential biological functions based on in-vitro experiments. Our analysis demonstrated that alternatively spliced transcripts of not only PKM but also other genes should be considered in cancer studies, since it may enable the discovery and targeting of the right protein product for development of the efficient treatment strategies. 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.

PKM

transcriptomics

cancer

alternative splicing

Author

Xiangyu Li

Royal Institute of Technology (KTH)

Woonghee Kim

Royal Institute of Technology (KTH)

Muhammad Arif

Royal Institute of Technology (KTH)

Chunxia Gao

University of Gothenburg

Andreas Hober

Royal Institute of Technology (KTH)

David Kotol

Royal Institute of Technology (KTH)

Linnea Strandberg

Royal Institute of Technology (KTH)

Bjorn Forsstrom

Royal Institute of Technology (KTH)

Asa Sivertsson

Royal Institute of Technology (KTH)

Per Oksvold

Royal Institute of Technology (KTH)

Hasan Turkez

Atatürk University

Morten Grotli

University of Gothenburg

Yusuke Sato

Kyoto University

University of Tokyo

Haruki Kume

University of Tokyo

Seishi Ogawa

Kyoto University

Karolinska Institutet

Jan Boren

University of Gothenburg

Jens B Nielsen

BioInnovation Institute

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Mathias Uhlen

Royal Institute of Technology (KTH)

Cheng Zhang

Royal Institute of Technology (KTH)

Zhengzhou University

Adil Mardinoglu

Royal Institute of Technology (KTH)

King's College London

Cancers

2072-6694 (ISSN)

Vol. 13 2 348

Subject Categories

Cell and Molecular Biology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Cancer and Oncology

DOI

10.3390/cancers13020348

PubMed

33478099

More information

Latest update

2/18/2021