Abstract
The switch of pyruvate kinase (PK) M1 to PKM2 is pivotal for glucose metabolism in cancers. The PKM1/M2 shift is controlled by the alternative splicing of two mutually exclusive exons in the PKM gene. PKM1 is expressed in differentiated tissues, whereas PKM2 is expressed in cancer tissues. This study revealed that the haplodeficiency of FUSE-binding protein (FBP)-interacting repressor (FIR), a transcriptional repressor of the c-myc gene, contributed to the splicing of PKM1 to PKM2 in mice thymic lymphoma and/or T-cell type acute lymphoblastic leukemia (T-ALL) using six-plex tandem mass tag (TMT) quantitative proteomic analysis. TMT revealed 648 proteins that were up- or downregulated in mice thymic lymphoma tissues compared with wild type mouse. These proteins included transcription factors and proteins involved in DNA damage repair, DNA replication, T-cell activation/proliferation, apoptosis, etc. Among them, PKM2 protein, but not PKM1, was upregulated in the thymic lymphoma as well as T-ALL. Using qRT-PCR, we revealed that the activation of PKM2 mRNA was higher in thymic lymphoma cells of FIR+/−TP53−/− mice than that in control lymphocytes of FIR+/+TP53−/− sorted by flow cytometry. FIR knockdown by siRNA suppressed hnRNPA1 expression in HeLa cells. These results indicated that FIR haplodeficiency contributes the alternative splicing of PKM1 to PKM2 by partly inhibiting hnRNPA1 expression in the thymic lymphoma cells prior to T-ALL. Taken together, our findings suggest that FIR and its related spliceosomes are potential therapeutic targets for cancers, including T-ALL.
Highlights
Pyruvate kinase (PK) M2 is activated in cancers through alternative splicing
This study revealed that the haplodeficiency of FUSE-binding protein (FBP)-interacting repressor (FIR), a transcriptional repressor of the c-myc gene, contributed to the splicing of PKM1 to PKM2 in mice thymic lymphoma and/or T-cell type acute lymphoblastic leukemia (T-ALL) using six-plex tandem mass tag (TMT) quantitative proteomic analysis
Using Quantitative real-time PCR (qRT-PCR), we revealed that the activation of PKM2 mRNA was higher in thymic lymphoma cells of FBP-interacting receptor (FIR)+/−TP53−/− mice than that in control lymphocytes of FIR+/+TP53−/− sorted by flow cytometry
Summary
Pyruvate kinase (PK) M2 is activated in cancers through alternative splicing. PKM2 activation supports aerobic glycolysis: the so-called “Warburg effect” [1]. The PKM1/M2 splicing switch is affected by many factors, including c-Myc [2]; the mechanism of the PKM1 switch to PKM2 in carcinogenesis is largely unclear. Interacting receptor (FIR) affects the splicing of PKM1 to PKM2, at least in part, in mice, as shown by six-plex tandem mass tag (TMT) quantitative proteomic analysis. C-Myc is a transcription factor that has several functions, including cell proliferation, differentiation, tumorigenesis, apoptosis, and cell cycle control [3]. The activation of c-Myc is frequently observed in many malignancies and places a burden on RNA and protein synthesis as well as affects metabolism even during pro-tumor stages [4].
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