HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer.
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.
David
Charles J
CJ
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Chen
Mo
M
Assanah
Marcela
M
Canoll
Peter
P
Manley
James L
JL
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D016259:Genes, myc; D006019:Glycolysis; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C439768:hnRNP A2; D038941:Polypyrimidine Tract-Binding Protein; D011770:Pyruvate Kinase