HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer

By Charles J. David, Mo Chen, Marcela C. Assanah, P. Canoll, J. Manley. Nature, 2009

1,135 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8c813b02b366e6d63feae69f143edea2fb4b07e9

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Citations in the corpus

Targeting lactate metabolism for cancer therapeutics. (2013, background): “Fourth, MYC induces the transcription of select splicing factors to promote production of PKM2, a normally embryonic isoform of pyruvate kinase that is catalytically inefficient and favors aerobic glycolysis (19, 20).”
Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth (2011, background): “Recently, the PKM1-to-PKM2 switch was found to be regulated by the Myc oncogene (David et al., 2009), providing further evidence linking the re-expression of the M2 isoform to the tumorigenesis.”
Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme (2011, methodology): “To address this, we performed a PKM2 splice assay (David et al., 2010) and found that the percentage of PKM2 over total PKM1 AND PKM2 did not change significantly with loss of HK2 or HK1 (Fig.”
Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. (2010, background): “Importantly, hnRNP A1 has been shown to be up-regulated in a wide variety of cancers, including breast, colorectal, and lung, and, as described above, gliomas (Pino et al. 2003; Ushigome et al. 2005; Li et al. 2009; David et al. 2010).”
Pyruvate Kinase M2 is a PHD3-stimulated Coactivator for Hypoxia-Inducible Factor 1 (2011, positive): “Heterogeneous nuclear ribonucleoproteins (hnRNP) I, A1, and A2 bind to RNA sequences encoded by exon 9 and inhibit PKM1 mRNA splicing (David et al., 2010).”
Regulation of cancer cell metabolism (2011, background): “The inclusion of exon 9 in the PK mRNA leads to translation of the PKM1 isoform, whereas inclusion of exon 10 produces PKM2 (Ref”
MYC, metabolism, cell growth, and tumorigenesis. (2013, background): “In addition to the ability of MYC to induce glycolytic genes, MYC has also been implicated in promoting RNA splicing for the expression of pyruvate kinase M2 (PKM2), which has been associated with proliferating cells, versus the alternative form, PKM1 (David et al. 2010).”
Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients (2018, background): “While alternative splicing of exon 9 exclusion giving rise to a change from PKM into PKM2 has been reported previously (Clower et al., 2010; David et al., 2010), suggesting a role not only in the alteration of metabolic function but also in tumor cell proliferation, we detect alternative 30 site…”
RNA-Binding Proteins in Cancer: Old Players and New Actors. (2017, background): “An additional case of the link between splicing defects and tumorigenesis is provided by the splicing factor hnRNPA2 that is overexpressed in gliomas and is also correlated with poor prognosis [42,43,67].”