HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer
Open accessAbstract
When oxygen is abundant, quiescent cells efficiently extract energy from glucose primarily by oxidative phosphorylation, whereas under the same conditions tumour cells consume glucose more avidly, converting it to lactate. This long-observed phenomenon is known as aerobic glycolysis, and is important for cell growth. Because aerobic glycolysis is only useful to growing cells, it is tightly regulated in a proliferation-linked manner. In mammals, this is partly achieved through control of pyruvate kinase isoform expression. The embryonic pyruvate kinase isoform, PKM2, is almost universally re-expressed in cancer, and promotes aerobic glycolysis, whereas the adult isoform, PKM1, promotes oxidative phosphorylation. These two isoforms result from mutually exclusive alternative splicing of the PKM pre-mRNA, reflecting inclusion of either exon 9 (PKM1) or exon 10 (PKM2). Here we show that three heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, polypyrimidine tract binding protein (PTB, also known as hnRNPI), hnRNPA1 and hnRNPA2, bind repressively to sequences flanking exon 9, resulting in exon 10 inclusion. We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, ensuring a high PKM2/PKM1 ratio. Establishing a relevance to cancer, we show that human gliomas overexpress c-Myc, PTB, hnRNPA1 and hnRNPA2 in a manner that correlates with PKM2 expression. Our results thus define a pathway that regulates an alternative splicing event required for tumour cell proliferation.
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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 David et al., 2010
MYC promotes a high PKM2/PKM1 ratio by upregulating heterogeneous nuclear ribonucleoproteins (hnRNP) that regulate PKM alternative splicing.
“MYC also promotes a high PKM2/PKM1 ratio by upregulating heterogeneous nuclear ribonucleoproteins (hnRNP) that regulate PKM alternative splicing (David et al., 2010).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as David et al., 2010
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- Authors
- David, C. J., Chen, M., Assanah, M., Canoll, P., & Manley, J. L.
- Affiliations
- Columbia University (US)
- Corresponding author
- Manley, James L.
- Venue
- Nature
- Published
- 2009-12-13
- Volume
- 463
- Issue
- 7279
- Pages
- 364-368
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2950088
- OpenAlex
- W2048255587
- Cited by
- 1,179
- References
- 31
- Citations by year
- 2026: 39 · 2025: 59 · 2024: 94 · 2023: 87 · 2022: 79 · 2021: 87 · 2020: 91 · 2019: 79 · 2018: 70 · 2017: 67 · 2016: 74 · 2015: 83 · 2014: 63 · 2013: 72 · 2012: 61
- FWCI
- 17.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM048259)
- 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, PKM2, PKM1, alternative splicing, c-Myc, hnRNP proteins, PTB, hnRNP A1, hnRNP A2, aerobic glycolysis, oxidative phosphorylation, cancer metabolism, tumor suppressor, tumor suppressor microRNA, tumor suppressor lncRNA
- MeSH terms
- Animals, Exons, Glycolysis, Humans, Neoplasms, Oxidative Phosphorylation, Protein Binding, Pyruvate Kinase, RNA, Messenger, Genes, myc, Proto-Oncogene Proteins c-myc, Alternative Splicing, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Polypyrimidine Tract-Binding Protein, NIH 3T3 Cells, Cell Line, Tumor, Mice
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