A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism

Abstract

Mitochondrial pyruvate carrier 1 (MPC-1) appears to be a tumor suppressor. In this study, we determined the regulation of MPC-1 expression by Lysine demethylase 5A (KDM5A) and critical impact of this novel KDM5A/MPC-1 signaling on PDA progression. TCGA database, paired PDA and adjacent normal pancreatic tissues, PDA tissue array and cell lines were used to determine the levels of MPC-1 and KDM5A expression, and their relationship with the clinicopathologic characteristics and overall survival (OS) of PDA patients. Both in vitro and in vivo models were used to determine biologic impacts of MPC-1 and KDM5A on PDA and mitochondrial pyruvate metabolism, and the mechanism underling reduced MPC-1 expression in PDA. The expression of MPC-1 was decreased in PDA cell lines and tissues, and negatively associated with tumor poorer differentiation, lymph nodes metastasis, higher TNM stages, and patients’ overall survival (OS). Functional analysis revealed that restored expression of MPC-1 suppressed the growth, invasion, migration, stemness and tumorigenicity. Re-expression of MPC-1 stimulated the mitochondrial pyruvate metabolism and inhibited glycolysis, while MPC-1-specific inhibitor UK5099 attenuated these effects. Furthermore, KDM5A bound directly to MPC-1 promoter region and transcriptionally suppressed the expression of MPC-1 via demethylation H3K4. Consistently, KDM5A expression was elevated in PDA and promoted PDA cell proliferation in vitro and tumor growth in vivo via suppressing the expression of MPC-1. The expression of KDM5A was inversely correlated with that of MPC-1 in PDA. KDM5A/MPC-1 signaling promoted PDA growth, invasion, migration, and stemness via inhibiting mitochondrial pyruvate metabolism. Targeting KDM5A/MPC-1 signaling may be an effective therapeutic strategy for PDA.

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References

  1. 1.

    Aguirre-Gamboa R, Gomez-Rueda H, Martinez-Ledesma E, Martinez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A, et al. SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS ONE. 2013;8:e74250.

  2. 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

  3. 3.

    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.

  4. 4.

    Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.

  5. 5.

    Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.

  6. 6.

    Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17:500–3.

  7. 7.

    Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–70.

  8. 8.

    Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell. 2015;162:540–51.

  9. 9.

    Flavell RB. Mitochondrion as a multifunctional organelle. Nature. 1971;230:504–6.

  10. 10.

    Martinez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell. 2016;61:199–209.

  11. 11.

    Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell. 2015;162:552–63.

  12. 12.

    Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science. 2012;337:96–100.

  13. 13.

    Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science. 2012;337:93–6.

  14. 14.

    Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell. 2014;56:400–13.

  15. 15.

    Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol. 2017;19:1027–36.

  16. 16.

    Li Y, Li X, Kan Q, Zhang M, Xu R, Wang J, et al. Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas. Oncotarget. 2017;8:1058–73.

  17. 17.

    Shannon CE, Daniele G, Galindo C, Abdul-Ghani MA, DeFronzo RA, Norton L. Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. FEBS J. 2017;284:451–65.

  18. 18.

    Mair B, Kubicek S, Nijman SM. Exploiting epigenetic vulnerabilities for cancer therapeutics. Trends Pharm Sci. 2014;35:136–45.

  19. 19.

    Tzatsos A, Paskaleva P, Ferrari F, Deshpande V, Stoykova S, Contino G, et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J Clin Invest. 2013;123:727–39.

  20. 20.

    Yamamoto K, Tateishi K, Kudo Y, Sato T, Yamamoto S, Miyabayashi K, et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPalpha. Carcinogenesis. 2014;35:2404–14.

  21. 21.

    Blair LP, Cao J, Zou MR, Sayegh J, Yan Q. Epigenetic regulation by lysine demethylase 5 (KDM5) enzymes in cancer. Cancers (Basel). 2011;3:1383–404.

  22. 22.

    Lopez-Bigas N, Kisiel TA, Dewaal DC, Holmes KB, Volkert TL, Gupta S, et al. Genome-wide analysis of the H3K4 histone demethylase RBP2 reveals a transcriptional program controlling differentiation. Mol Cell. 2008;31:520–30.

  23. 23.

    Peng JC, Valouev A, Swigut T, Zhang J, Zhao Y, Sidow A, et al. Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell. 2009;139:1290–302.

  24. 24.

    Varaljai R, Islam AB, Beshiri ML, Rehman J, Lopez-Bigas N, Benevolenskaya EV. Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells. Genes Dev. 2015;29:1817–34.

  25. 25.

    Takaoka Y, Konno M, Koseki J, Colvin H, Asai A, Tamari K, et al. Mitochondrial pyruvate carrier 1 expression controls cancer epithelial-mesenchymal transition and radioresistance. Cancer Sci. 2019;110:1331–9.

  26. 26.

    Zou H, Chen Q, Zhang A, Wang S, Wu H, Yuan Y, et al. MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway. Cell Death Dis. 2019;10:148.

  27. 27.

    Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J, et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 2014;56:414–24.

  28. 28.

    Beshiri ML, Holmes KB, Richter WF, Hess S, Islam AB, Yan Q, et al. Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation. Proc Natl Acad Sci USA. 2012;109:18499–504.

  29. 29.

    Howe FS, Fischl H, Murray SC, Mellor J. Is H3K4me3 instructive for transcription activation? Bioessays. 2017;39:1–12.

  30. 30.

    Tu S, Teng YC, Yuan C, Wu YT, Chan MY, Cheng AN, et al. The ARID domain of the H3K4 demethylase RBP2 binds to a DNA CCGCCC motif. Nat Struct Mol Biol. 2008;15:419–21.

  31. 31.

    Lofrumento NE, Papa S, Zanotti F, Kanduc D, Quagliariello E. [Properties of systems of transport of anionic substrates in mitochondria]. Boll Soc Ital Biol Sper. 1971;47:676–80.

  32. 32.

    Brivet M, Garcia-Cazorla A, Lyonnet S, Dumez Y, Nassogne MC, Slama A, et al. Impaired mitochondrial pyruvate importation in a patient and a fetus at risk. Mol Genet Metab. 2003;78:186–92.

  33. 33.

    Li X, Ji Y, Han G, Fan Z, Li Y, Zhong Y, et al. MPC1 and MPC2 expressions are associated with favorable clinical outcomes in prostate cancer. BMC Cancer. 2016;16:894.

  34. 34.

    Pasini D, Hansen KH, Christensen J, Agger K, Cloos PA, Helin K. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and polycomb-repressive complex 2. Genes Dev. 2008;22:1345–55.

  35. 35.

    Defeo-Jones D, Huang PS, Jones RE, Haskell KM, Vuocolo GA, Hanobik MG, et al. Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature. 1991;352:251–4.

  36. 36.

    Gong F, Clouaire T, Aguirrebengoa M, Legube G, Miller KM. Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. J Cell Biol. 2017;216:1959–74.

  37. 37.

    Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007;128:889–900.

  38. 38.

    Wang C, Wang J, Li J, Hu G, Shan S, Li Q, et al. KDM5A controls bone morphogenic protein 2-induced osteogenic differentiation of bone mesenchymal stem cells during osteoporosis. Cell Death Dis. 2016;7:e2335.

  39. 39.

    Zhao D, Zhang Q, Liu Y, Li X, Zhao K, Ding Y, et al. H3K4me3 demethylase Kdm5a is required for NK cell activation by associating with p50 to suppress SOCS1. Cell Rep. 2016;15:288–99.

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Funding

This work was supported by grants 81502018 (to JC), 81502043 (to MQ) and 81602051 (to DX) from National Natural Science Foundation of China; grant [2019]72 (to JC) from Shanghai “Rising Stars of Medical Talent” Youth Development Program, Youth Medical Talents-Specialist Program; Fundamental Research Funds for the Central Universities 22120180029 (to MQ); The Outstanding Clinical Discipline Project of Shanghai Pudong (Grant No. PWYgy2018-02).

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Correspondence to Ming Quan or Jingde Chen or Keping Xie.

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Cui, J., Quan, M., Xie, D. et al. A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism. Oncogene 39, 1140–1151 (2020). https://doi.org/10.1038/s41388-019-1051-8

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