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MicroRNA 675 cooperates PKM2 to aggravate progression of human liver cancer stem cells induced from embryonic stem cells

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Abstract

Both miR675 and pyruvate kinase M2 (PKM2) contribute to malignant progression of tumor, but its functions in liver cancer stem cells remain unclear. Herein, our findings indicate that miR675 plus PKM2 strongly promotes the growth of liver cancer stem cells. Mechanistically, miR675 plus PKM2 enhances the transcriptional activity of SUV39h2. On the other hand, the excessive SUV39h2 binds to more substrate histone H3, triggering an increase of tri-methylation of histone H3 on the ninth lysine. Furthermore, the tri-methylation of histone 3 on the ninth lysine (H3K9me3)-heterochromatin protein 1 alpha (HP1α) complex is increased when the complex occupancy ability on the C-myc promoter region is raised, recruiting CREB, P300, and RNApolII to the special position that results in C-myc high abundance. Therefore, miR675 plus PKM2 triggered the upregulation of C-myc by increasing the interaction between H3K9me3 and HP1α. Understanding the signaling pathways that miR675 plus PKM2 epigenetically possesses during the malignant transformation of liver cancer stem cells will contribute to more effective liver cancer therapies.

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References

  1. Keniry A, Oxley D, Monnier P, Kyba M, Dandolo L, Smits G, Reik W (2012) The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol 14(7):659–665

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Kim NH, Choi SH, Lee TR, Lee CH, Lee AY (2014) Cadherin 11, a miR-675 target, induces N-cadherin expression and epithelial-mesenchymal transition in melasma. J Invest Dermatol 134(12):2967–2976

    Article  PubMed  CAS  Google Scholar 

  3. Shi Y, Wang Y, Luan W, Wang P, Tao T, Zhang J, Qian J, Liu N, You Y (2014) Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One 9(1):e86295

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Goodell MA (2013) Parental permissions: H19 and keeping the stem cell progeny under control. Cell Stem Cell. 13(2):137–138

    Article  PubMed  CAS  Google Scholar 

  5. Gao WL, Liu M, Yang Y, Yang H, Liao Q, Bai Y, Li YX, Li D, Peng C, Wang YL (2012) The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1). RNA Biol 9(7):1002–1010

    Article  PubMed  CAS  Google Scholar 

  6. Schmitz KJ, Helwig J, Bertram S, Sheu SY, Suttorp AC, Seggewiss J, Willscher E, Walz MK, Worm K, Schmid KW (2011) Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours. J Clin Pathol 64(6):529–535

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Shi J, Dong B, Cao J, Mao Y, Guan W, Peng Y, Wang S (2017) Long non-coding RNA in glioma: signaling pathways. Oncotarget 8(16):27582–27592

    Article  PubMed  PubMed Central  Google Scholar 

  8. Huang Y, Zheng Y, Jin C, Li X, Jia L, Li W (2016) Long non-coding RNA H19 inhibits adipocyte differentiation of bone marrow mesenchymal stem cells through epigenetic modulation of histone deacetylases. Sci Rep 6:28897

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zhou YW, Zhang H, Duan CJ, Gao Y, Cheng YD, He D, Li R, Zhang CF (2016) miR-675-5p enhances tumorigenesis and metastasis of esophageal squamous cell carcinoma by targeting REPS2. Oncotarget 7(21):30730–30747

    PubMed  PubMed Central  Google Scholar 

  10. Vennin C, Spruyt N, Dahmani F, Julien S, Bertucci F, Finetti P, Chassat T, Bourette RP, Le Bourhis X, Adriaenssens E (2015) H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b. Oncotarget 6(30):29209–29223

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hernandez JM, Elahi A, Clark CW, Wang J, Humphries LA, Centeno B, Bloom G, Fuchs BC, Yeatman T, Shibata D (2013) miR-675 mediates downregulation of Twist1 and Rb in AFP-secreting hepatocellular carcinoma. Ann Surg Oncol 20(Suppl 3):S625–S635

    Article  PubMed  Google Scholar 

  12. Li H, Li J, Jia S, Wu M, An J, Zheng Q, Zhang W, Lu D (2015) miR675 upregulates long noncoding RNA H19 through activating EGR1 in human liver cancer. Oncotarget 6(31):31958–31984

    PubMed  PubMed Central  Google Scholar 

  13. Wong N, De Melo J, Tang D (2013) PKM2, a central point of regulation in cancer metabolism. Int J Cell Biol. 2013:242513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Wong N, Ojo D, Yan J, Tang D (2015) PKM2 contributes to cancer metabolism. Cancer Lett 356(2 Pt A):184–191

    Article  PubMed  CAS  Google Scholar 

  15. Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung HJ, Wang WC (2014) JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci U S A 111(1):279–284

    Article  PubMed  CAS  Google Scholar 

  16. Li L, Zhang Y, Qiao J, Yang JJ, Liu ZR (2014) Pyruvate kinase M2 in blood circulation facilitates tumor growth by promoting angiogenesis. J Biol Chem 289(37):25812–25821

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Keller KE, Doctor ZM, Dwyer ZW, Lee YS (2014) SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol Cell 53(5):700–709

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Jiang Y, Li X, Yang W, Hawke DH, Zheng Y, Xia Y, Aldape K, Wei C, Guo F, Chen Y, Lu Z (2014) PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell 53(1):75–87

    Article  PubMed  CAS  Google Scholar 

  19. Gui X, Li H, Li T, Pu H, Dongdong L (2015) Long noncoding RNA CUDR regulates HULC and β-catenin to govern human liver stem cell malignant differentiation. Mol Ther 23(12):1843–1853

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Li T, Zheng Q, An J, Wu M, Li H, Xin Gui HP, Dongdong L (2016) SET1A cooperates with CUDR to promote liver cancer growth and hepatocyte-like stem cell malignant transformation epigenetically. Mol Ther 24(2):261–275

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Zheng Q, Lin Z, Li X, Xin X, Wu M, An J, Gui X, Tianming Li HP, Li H, Dongdong L (2016) Inflammatory cytokine IL6 cooperates with CUDR to aggravate hepatocyte-like stem cells malignant transformation through NF-κB signaling. Sci Rep 6:36843

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhuang M, Gao W, Xu J, Wang P, Shu Y (2014) The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1. Biochem Biophys Res Commun 448(3):315–322

    Article  PubMed  CAS  Google Scholar 

  23. Canzio D, Liao M, Naber N, Pate E, Larson A, Wu S, Marina DB, Garcia JF, Madhani HD, Cooke R, Schuck P, Cheng Y, Narlikar GJ (2013) A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly. Nature 496(7445):377–381

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Cortés-Cros M, Hemmerlin C, Ferretti S, Zhang J, Gounarides JS, Yin H, Muller A, Haberkorn A, Chene P, Sellers WR, Hofmann F (2013) M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc Natl Acad Sci U S A 110(2):489–494

    Article  PubMed  Google Scholar 

  25. Wong CC, Au SL, Tse AP, Xu IM, Lai RK, Chiu DK, Wei LL, Fan DN, Tsang FH, Lo RC, Wong CM, Ng IO (2014) Switching of pyruvate kinase isoform L to m2 promotes metabolic reprogramming in hepatocarcinogenesis. PLoS One. 9(12):e115036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Alfred Yung WK, Lu Z (2012) PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150(4):685–696

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Lu Z (2012) ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14(12):1295–1304

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Liang J (2016) PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nat Commun 7:12431

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Park SH (2016) SIRT2-mediated deacetylation and tetramerization of pyruvate kinase directs glycolysis and tumor growth. Cancer Res 76(13):3802–3812

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wu M, An J, Zheng Q, Xin X, Lin Z, Li X, Li H, Lu D (2016) Double mutant P53 (N340Q/L344R) promotes hepatocarcinogenesis through upregulation of Pim1 mediated by PKM2 and LncRNA CUDR. Oncotarget. 7(41):66525–66539

    PubMed  PubMed Central  Google Scholar 

  31. Azoitei N (2016) PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation. Mol Cancer 15:3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Yang YC (2016) Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association. Oncogene 35(26):3387–3398

    Article  PubMed  CAS  Google Scholar 

  33. Zhao Z (2016) PKM2 promotes stemness of breast cancer cell by through Wnt/β-catenin pathway. Tumour Biol 37(3):4223–4234

    Article  PubMed  CAS  Google Scholar 

  34. Smallwood A, Hon GC, Jin F, Henry RE, Espinosa JM, Ren B (2012) CBX3 regulates efficient RNA processing genome-wide. Genome Res 22(8):1426–1436

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Munari F, Soeroes S, Zenn HM, Schomburg A, Kost N, Schröder S, Klingberg R, Rezaei-Ghaleh N, Stützer A, Gelato KA, Walla PJ, Becker S, Schwarzer D, Zimmermann B, Fischle W, Zweckstetter M (2012) Methylation of lysine 9 in histone H3 directs alternative modes of highly dynamic interaction of heterochromatin protein hHP1β with the nucleosome. J Biol Chem 287(40):33756–33765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Yu YH, Chiou GY, Huang PI, Lo WL, Wang CY, Lu KH, Yu CC, Alterovitz G, Huang WC, Lo JF, Hsu HS, Chiou SH (2012) Network biology of tumor stem-like cells identified a regulatory role of CBX5 in lung cancer. Sci Rep 2:584

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Liu J, Yin X, Liu B, Zheng H, Zhou G, Gong L, Li M, Li X, Wang Y, Hu J, Krishnan V, Zhou Z, Wang Z (2014) HP1α mediates defective heterochromatin repair and accelerates senescence in Zmpste24-deficient cells. Cell Cycle 13(8):1237–1247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Chakraborty A, Prasanth SG (2014) Phosphorylation-dephosphorylation cycle of HP1α governs accurate mitotic progression. Cell Cycle 13(11):1663–1670

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Itsumi M, Shiota M, Yokomizo A, Kashiwagi E, Takeuchi A, Tatsugami K, Inokuchi J, Song Y, Uchiumi T, Naito S (2013) Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer. J Mol Endocrinol 50(3):401–409

    Article  PubMed  CAS  Google Scholar 

  40. Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, Ronning P, Reuland B, Guenther K, Beadnell TC, Essig J, Otto GM, O’Sullivan MG, Largaespada DA, Schwertfeger KL, Marahrens Y, Kawakami Y, Bagchi A (2014) PVT1 dependence in cancer with MYC copy-number increase. Nature 512(7512):82–86

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wüstefeld T, Fischer M, Teichmann M, Zender L, Wei CL, Sansom O, Wolf E, Eilers M (2014) Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 511(7510):483–487

    Article  PubMed  CAS  Google Scholar 

  42. Ma MZ, Li CX, Zhang Y, Weng MZ, Zhang MD, Qin YY, Gong W, Quan ZW (2014) Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol Cancer 13:156

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Zhang Q, Spears E, Boone DN, Li Z, Gregory MA, Hann SR (2013) Domain-specific c-Myc ubiquitylation controls c-Myc transcriptional and apoptotic activity. Proc Natl Acad Sci U S A 110(3):978–983

    Article  PubMed  Google Scholar 

  44. Li Y, Choi PS, Casey SC, Dill DL, Felsher DW (2014) MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell 26(2):262–272

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Amelio AL, Fallahi M, Schaub FX, Zhang M, Lawani MB, Alperstein AS, Southern MR, Young BM, Wu L, Zajac-Kaye M, Kaye FJ, Cleveland JL, Conkright MD (2014) CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci U S A 111(32):E3260–E3268

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Janghorban M, Farrell AS, Allen-Petersen BL, Pelz C, Daniel CJ, Oddo J, Langer EM, Christensen DJ, Sears RC (2014) Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer. Proc Natl Acad Sci U S A 111(25):9157–9162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Zhong J, Ding L, Bohrer LR, Pan Y, Liu P, Zhang J, Sebo TJ, Karnes RJ, Tindall DJ, van Deursen J, Huang H (2014) p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis. Cancer Res 74(6):1870–1880

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

This study was supported by grants from the National Natural Science Foundation of China (NCSF Nos. 81773158 and 81572773).

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Authors and Affiliations

  1. Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200092, China

    Yuxin Yang, Qiuyu Meng, Chen Wang, Xiaonan Li, Yanan Lu, Xiaoru Xin, Qidi Zheng & Dongdong Lu

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  1. Yuxin Yang
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  2. Qiuyu Meng
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  3. Chen Wang
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  4. Xiaonan Li
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Correspondence to Dongdong Lu.

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Yang, Y., Meng, Q., Wang, C. et al. MicroRNA 675 cooperates PKM2 to aggravate progression of human liver cancer stem cells induced from embryonic stem cells. J Mol Med 96, 1119–1130 (2018). https://doi.org/10.1007/s00109-018-1687-9

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