The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism
Open accessAbstract
Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production. This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase, in contrast to the M1 isozyme normally expressed in differentiated cells, and it confers a proliferative advantage to tumor cells. The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons. We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues, tumor cell lines, and during terminal differentiation of muscle cells, and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms. We further show that the M1-specific exon is actively repressed in cancer-cell lines--although some M1 mRNA is expressed in cell lines derived from brain tumors--and demonstrate that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to this control. Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production. These findings extend the links between alternative splicing and cancer, and begin to define some of the factors responsible for the switch to aerobic glycolysis.
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PKM splicing or the PKM2/PKM1 ratio is controlled by expression levels of hnRNPI, hnRNPA1 and hnRNPA2, which bind repressively to sequences flanking exon 9, favoring exon 10 addition and generating more PKM2 in cancer cells.
“PKM splicing or the PKM2/PKM1 ratio is known to be controlled by the expression levels of nuclear ribonucleoprotein (hnRNP) proteins, hnRNPI, hnRNPA1 and hnRNPA2, and in cancer cells, these proteins are expressed at high levels and bind repressively to the sequences flanking exon 9, favoring the exon 10 addition thus generating more PKM2”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Clower et al., 2010
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- Authors
- Clower, C. V., Chatterjee, D., Wang, Z., Cantley, L. C., Vander Heiden, M. G., & Krainer, A. R.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Cold Spring Harbor Laboratory (US)
- Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-01-19
- Volume
- 107
- Issue
- 5
- Pages
- 1894-1899
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2838216
- OpenAlex
- W2152445360
- Cited by
- 424
- References
- 30
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 28 · 2023: 26 · 2022: 22 · 2021: 34 · 2020: 27 · 2019: 30 · 2018: 27 · 2017: 24 · 2016: 27 · 2015: 30 · 2014: 30 · 2013: 27 · 2012: 30
- FWCI
- 12.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (T32CA009172)
- National Institute of General Medical Sciences (R01GM056203)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pyruvate kinase, alternative splicing, splicing repressor, polypyrimidine tract-binding protein, aerobic glycolysis, cancer metabolism, lactic acid production, myogenesis, cancer cell lines, brain tumors, shRNA knockdown
- MeSH terms
- Heterogeneous Nuclear Ribonucleoprotein A1, Aerobiosis, Animals, Cell Line, Exons, Glioblastoma, Glycolysis, HeLa Cells, Humans, Isoenzymes, Pyruvate Kinase, Repressor Proteins, RNA, Messenger, Alternative Splicing, Lactic Acid, RNA Splice Sites, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Polypyrimidine Tract-Binding Protein, Cell Line, Tumor, Mice
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