Abstract
Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1–PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.
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Change history
13 November 2017
In the version of this Article originally published, an amino acid (aa) range in Fig. 2a incorrectly read 390–53 aa. The correct range is 390–531 aa. In addition, two labels from Fig. 8j were displaced during production and instead appeared over Fig. 8g. These errors have now been corrected in the online version of the Article.
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Acknowledgements
We thank M. G. Vander Heiden for kindly providing the immortalized MEF (PKM2fl/fl, Cre-oestrogen receptor) cells, J. Massagué for kindly providing the LM2 cells, N. Sherer for fluorescence microscopy, C. Coriano and J. Fan for comments, and P. Ahlquist for editing. This project is supported by NCI RO1 CA213293 to W.X. and R21 CA196653 to W.X. and S.G., and supported in part by the NIH/NCI P30CA014520 -UW Carbone Cancer Center Grant, and NIH R01 DK071801 to L.L., S10RR029531 and P41GM108538.
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W.X. and F.L. conceived the project, designed the experiments, analysed the data and wrote the manuscript. F.L. performed the experiments with assistance from H.Z., B.L., J.J. and Yidan W. F.M., L.H. and C.J. performed the mass spectrometry experiments; Yuyuan W., G.C. and S.G. designed the nanoparticles. P.L. and I.M.O. performed bioinformatics analyses; W.X., L.L. and S.G. directed and supervised all aspects of the study; all authors discussed the results and commented on the manuscript.
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Integrated supplementary information
Supplementary Figure 1 CARM1 KO decreases EdU incorporation and increases OCR in MCF7 cells.
(a) EdU incorporation assays in parental MCF7 and CARM1 KO cells (n = 3 independent experiments). Cells were incubated with 10 μM EdU for 1 hour prior to flow cytometric analysis. (b,c) Basal OCR values normalized to cell numbers in parental MCF7 and CARM1 KO cells (b) or in parental MDA-MB-231 and CARM1 KO cells (c) (n = 6 independent experiments). (d,e) Relative lactate production in parental MCF7 and CARM1 KO cells (d) or in parental MDA-MB-231 and CARM1 KO cells (e) (n = 3 independent experiments). (f) Relative glucose uptake in parental MCF7 and CARM1 KO cells (n = 3 independent experiments). In a–f, data are shown as Mean ± SD and statistics source data are available in Supplementary Table 7. Statistical significance was assessed using two-tailed t-test. ∗∗p < 0.01, ns: not significant.
Supplementary Figure 2 TEPP-46 promotes PKM2 tetramer formation whereas R445/447/455K mutations on neither PKM1 nor PKM2 alter their di-/tetra-merization status.
(a) PDB structure of PKM2 tetramer (PDB ID: 3SRH) showing the positions of R445, 447 and 455 residues. Neither of the three R methylation sites is localized to the tetrameric interface. (b) Size exclusion chromatography and western blot analyses of His-tagged PKM2 in the presence and absence of TEPP-46 treatment. Wild type PKM2 and PKM2 R445/447/455K mutant peaks are completely overlapped. (c) Size exclusion chromatography and western blot analyses of His-tagged PKM1 and the corresponding R445/447/455K mutant. Mutations at R methylation sites do not alter PKM1 tetramer status. In b,c, data represent one of the two independent experiments with similar results. Unprocessed original scans of blots are shown in Supplementary Figure 9.
Supplementary Figure 3 Characterization of PKM2 KO clones.
(a) Genomic DNA sequencing results of selected PKM2 KO clones shows frame-shifts in PKM2 specific exon, resulting in knockout of PKM2 in MCF7 and MDA-MB-231 cells. (b) The relative pyruvate kinase activity in parental and MCF7 PKM2 KO clones (n = 3 independent experiments). (c) The relative pyruvate kinase activity in parental MCF7, MCF7 CARM1 KO, parental MDA-MB-231 or MAD-MB-231 CARM1 KO cells (n = 3 independent experiments). (d) Cell growth measured by MTT assays in parental MCF7 and MCF7 cells overexpressing PKM1 (n = 10 independent experiments). (e) Western blot analysis of PKM1 in MCF7 PKM2 KO or MDA-MB-231 PKM2 KO cells expressing ctrl shRNA or PKM1 shRNA (#1 and 2). (f) Cell growth measured by MTT assays in MCF7 PKM2 KO cells with ctrl shRNA or PKM1 shRNA (#1) knockdown (n = 6 independent experiments). (g) Basal OCR values normalized to cell numbers in MCF7 PKM2 KO cells with ctrl shRNA or PKM1 shRNA (#1) knockdown (n = 3 independent experiments). (h) Western blot analysis of methylated PKM2 in immunoprecipitated PKM2 from parental and CARM1 KO cells. (i) Colony formation assays in parental MCF7, PKM2 KO, PKM2wt/shPKM1 and PKM2mut/shPKM1 cells. (j) Cell apoptosis measured by Annexin V and propidium iodide (PI) staining in parental MCF7, PKM2 KO, PKM2wt/shPKM1 and PKM2mut/shPKM1 cells. In b–d,f,h, data are shown as Mean ± SD and statistics source data are available in Supplementary Table 7. Statistical significance was assessed using two-tailed t-test (b,c,g) and ANOVA (d,f). ns: not significant. In e,h–j, data represent one of the three independent experiments with similar results. Unprocessed original scans of blots are shown in Supplementary Figure 9.
Supplementary Figure 4 Inhibition of PKM2 methylation leads to increase of mitochondrial ROS levels.
(a–c) The ROS levels in parental MCF7 and MCF7 PKM2 KO cells (a); MCF7 expressing PKM2wt/shPKM1 and PKM2mut/shPKM1 (b); parental MCF7 and CARM1 KO cells (c) (n = 3 independent experiments). (d,f) Relative NADPH/NADP + ratio (d) and GSH concentration (f) in parental MCF7, PKM2 KO, PKM2wt/shPKM1 and PKM2mut/shPKM1 cells (n = 3 independent experiments). (e,g) Relative NADPH/NADP + ratios (e) and GSH concentrations (g) in parental MCF7 and CARM1 KO cells (n = 3). (h,i) Relative NADPH/NADP + ratios (h) and GSH concentrations (i) in parental MDA-MB-231, PKM2 KO, PKM2wt/shPKM1 and PKM2mut/shPKM1 cells (n = 3 independent experiments). (j–l) Cell growth measured by MTT assays in MCF7 PKM2mut/shPKM1 (j) or MDA-MB-231 PKM2mut/shPKM1 (k) or MCF7 CARM1 KO (l) cells treated with mitoTEMPO (n = 10 independent experiments). (m) Images of migrated MDA-MB-231 PKM2mut/shPKM1 cells treated with mitoTEMPO. Scale bars, 50 μm. (n) Cell growth in MCF7 PKM2mut/shPKM1 or MDA-MB-231 PKM2mut/shPKM1 or MCF7 CARM1 KO cells treated with glutathione (1mM) (n = 3 independent experiments). (o) Images of migrated MDA-MB-231 PKM2mut/shPKM1 cells treated with glutathione. Scale bars, 50 μm. In a–l,n, data are shown as Mean ± SD and statistics source data are available in Supplementary Table 7. Statistical significance was assessed using two-tailed t-test (a–c,e,g) and ANOVA (d,f,h–l,n). In m,o, data represent one of the two independent experiments with similar results. ∗p < 0.05, ∗∗p < 0.01 ∗∗∗p < 0.001, ns: not significant.
Supplementary Figure 5 PKM2 methylation suppresses mitochondrial membrane potential and mitochondrial DNA content.
(a) Mitochondrial membrane potential (ΔΨ) measured by the incorporation of TMRE dye in MDA-MB-231 cells (n = 3 independent experiments). (b) Mitochondrial DNA (mtDNA) content in parental MCF7, PKM2 KO, PKM2wt/shPKM1 and PKM2mut/shPKM1 cells (n = 3 independent experiments). In a,b, data are shown as Mean ± SD and statistics source data are available in Supplementary Table 7. Statistical significance was assessed using ANOVA (a,b). ∗p < 0.05, ∗∗p < 0.01 ∗∗∗p < 0.001, ns: not significant.
Supplementary Figure 6 MAM localized PKM2 interacts with and suppresses IP3Rs expression in methylation-dependent manner.
(a) Western blot analyses of PKM1 and PKM2 in cytosolic and mitochondria fractions derived from parental MCF7 or PKM2 KO cells. VDAC and tubulin serve as mitochondria and cytoplasm markers, respectively. (b) Confocal images of PKM2 localization in mitochondria. HSPA9 serves as a positive control which largely overlap with PKM2 staining. (c) Western blot analyses of wild type or mutant PKM2 in cytosolic and mitochondria fractions from MCF7 PKM2wt/shPKM1 and PKM2mut/shPKM1 cells. (d) List of selected ER and mitochondrial proteins that interact with wild type PKM2 or methylation-defective PKM2. Flag-tagged wild type or mutant PKM2 were transiently transfected into HEK293T cells. Flag-tagged PKM2 was pulled down from cell lysates and the interacting proteins were analyzed by mass spectrometry. The numbers of the detected peptides for each protein are indicated. (e) Venn diagram of PKM2 interacting proteins identified in Supplementary Fig. 6d overlapped with the altered proteins in response to PKM2 KO in MCF7 cells (Fig. 3c). 22 PKM2 interacting proteins were upregulated and 13 PKM2 interacting proteins were downregulated. ITPRs are also known as IP3Rs. (f) Western blot analysis of IP3R1 and IP3R3 in MCF7 cells overexpressing Flag-PKM1. (g) Co-immunoprecipitation of IP3R3 with PKM2 from MCF7 and MDA-MB-231 cell lysates. (h) Western blot analyses of IP3R3 protein levels in parental MCF7, CARM1 KO, or parental MCF7 treated with DMSO or TEPP-46. (i) Q-PCR analyses of mRNA levels of IP3R1, IP3R2 and IP3R3 in parental MCF7 and MDA-MB-231 cells and their respective PKM2 KO clones (n = 3 independent experiments). Data are shown as Mean ± SD and statistics source data are available in Supplementary Table 7. In a–c,f–h, data represent one of the three independent experiments with similar results. Unprocessed original scans of blots are shown in Supplementary Figure 9.
Supplementary Figure 7 Methylated PKM2 restrains mitochondrial addiction to Ca2+ through IP3Rs.
(a) Western blot analysis of relative IP3R3 in MCF7 and MDA-MB-231 cells. (b) Western blot analysis of IP3R3 knockdown efficiency in MCF7 PKM2 KO and MDA-MB-231 cells. (c) The gating strategy of flow cytometry. (d) Representative images of parental MDA-MB-231, PKM2 KO, PKM2wt/shPKM1 and PKM2mut/shPKM1 cells after treatment with 5 μM XeB for 24 hours. Scale bars, 50 μm. In a,b, data represent one of the three independent experiments with similar results. Unprocessed original scans of blots are shown in Supplementary Figure 9.
Supplementary Figure 8 Cellular PKM2 methylation can be inhibited by unimolecular nanoparticle (UMNP) loaded with non-methyl-PKM2 peptide.
(a) Assessing the proportion of the endogenous methylated PKM2 by immunoprecipitation using the excess amount of methyl-PKM2 antibody. The amount of precipitated methyl-PKM2 is estimated by subtracting the PKM2 left in the flow-through (FT) fraction from the input following detection with PKM2 antibody. The western blot bands were quantified using ImageJ software. (b) The chemical structure of the unique unimolecular nanoparticles (UMNP) for PKM2 peptide delivery. (c) Illustration of the UMNP used for PKM2 peptide delivery. (d) Synthesis scheme of the multi-arm star block copolymer poly(amidoamine)–poly(aspartate diethyltriamine-aconitic acid-r-imidazole)-poly(ethylene glycol) (PAMAM-PAsp(DET-Aco-r-Im)-PEG-TAT). (e) 1H NMR spectrum of the multi-arm star block copolymer PAMAM-PAsp(DET-Aco-r-Im)-PEG-TAT. The * represents the solvent residual peak. (f) Dynamic light scattering (DLS) histogram of the UMNPs. (g) The relative pyruvate kinase activity of PKM2 in MDA-MB-231 cells treated with UMNP-methyl-peptide or UMNP-non-methyl-peptide (n = 3 independent experiments). Data are shown as Mean ± SD and statistics source data are available in Supplementary Table 7. Statistical significance was assessed using two-tailed t-test. ns: not significant. (h) The schematic diagram of energy homeostasis regulated by PKM2 methylation in cancer cells. CARM1 methylates dimeric PKM2 which associates with IP3Rs to inhibit Ca2+ influx from ER to mitochondria, resulting in increased PDH phosphorylation and decreased oxidative phosphorylation. Inhibiting PKM2 methylation by knocking out CARM1 or PKM2 or with a competitive PKM2 peptide increases IP3Rs expression, consequently increased [Ca2+]mito, de-phosphorylated PDH, and increased oxidative phosphorylation. The cell survival depends on [Ca2+]mito and is sensitive to IP3R inhibition. In a, data represent one of the three independent experiments with similar results. Unprocessed original scans of blots are shown in Supplementary Figure 9.
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Liu, F., Ma, F., Wang, Y. et al. PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis. Nat Cell Biol 19, 1358–1370 (2017). https://doi.org/10.1038/ncb3630
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DOI: https://doi.org/10.1038/ncb3630
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