Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers
Artikel i vetenskaplig tidskrift, 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

Författare

Xiangyu Li

Kungliga Tekniska Högskolan (KTH)

Woonghee Kim

Kungliga Tekniska Högskolan (KTH)

Muhammad Arif

Kungliga Tekniska Högskolan (KTH)

Chunxia Gao

Göteborgs universitet

Andreas Hober

Kungliga Tekniska Högskolan (KTH)

David Kotol

Kungliga Tekniska Högskolan (KTH)

Linnea Strandberg

Kungliga Tekniska Högskolan (KTH)

Bjorn Forsstrom

Kungliga Tekniska Högskolan (KTH)

Asa Sivertsson

Kungliga Tekniska Högskolan (KTH)

Per Oksvold

Kungliga Tekniska Högskolan (KTH)

Hasan Turkez

Atatürk Üniversitesi

Morten Grotli

Göteborgs universitet

Yusuke Sato

Kyoto University

University of Tokyo

Haruki Kume

University of Tokyo

Seishi Ogawa

Kyoto University

Karolinska Institutet

Jan Boren

Göteborgs universitet

Jens B Nielsen

BioInnovation Institute

Chalmers, Biologi och bioteknik, Systembiologi

Mathias Uhlen

Kungliga Tekniska Högskolan (KTH)

Cheng Zhang

Kungliga Tekniska Högskolan (KTH)

Zhengzhou University

Adil Mardinoglu

Kungliga Tekniska Högskolan (KTH)

King's College London

Cancers

2072-6694 (ISSN)

Vol. 13 2 348

Ämneskategorier

Cell- och molekylärbiologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

Cancer och onkologi

DOI

10.3390/cancers13020348

PubMed

33478099

Mer information

Senast uppdaterat

2021-02-18