DOI QR코드

DOI QR Code

Downregulation of SETD5 Suppresses the Tumorigenicity of Hepatocellular Carcinoma Cells

  • Park, Mijin (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology) ;
  • Moon, Byul (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology) ;
  • Kim, Jong-Hwan (Korea Bioinformation Center, KRIBB) ;
  • Park, Seung-Jin (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology) ;
  • Kim, Seon-Kyu (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology) ;
  • Park, Kihyun (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Kim, Jaehoon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Kim, Seon-Young (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology) ;
  • Kim, Jeong-Hoon (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology) ;
  • Kim, Jung-Ae (Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, University of Science and Technology)
  • 투고 : 2022.01.13
  • 심사 : 2022.03.04
  • 발행 : 2022.08.31

초록

Hepatocellular carcinoma (HCC) is an aggressive and incurable cancer. Although understanding of the molecular pathogenesis of HCC has greatly advanced, therapeutic options for the disease remain limited. In this study, we demonstrated that SETD5 expression is positively associated with poor prognosis of HCC and that SETD5 depletion decreased HCC cell proliferation and invasion while inducing cell death. Transcriptome analysis revealed that SETD5 loss downregulated the interferon-mediated inflammatory response in HCC cells. In addition, SETD5 depletion downregulated the expression of a critical glycolysis gene, PKM (pyruvate kinase M1/2), and decreased glycolysis activity in HCC cells. Finally, SETD5 knockdown inhibited tumor growth in xenograft mouse models. These results collectively suggest that SETD5 is involved in the tumorigenic features of HCC cells and that targeting SETD5 may suppress HCC progression.

키워드

과제정보

This work was supported by a grant (NRF-2019R1A2C 1086151 to J.-A.K.) from the National Research Foundation, Ministry of Science and ICT and Future Planning and by the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (171134054 to J.-A.K. and KGM99922111 to J.-H.K. [Jeong-Hoon Kim] and J.-A. K.).

참고문헌

  1. Abou-Alfa, G.K., Meyer, T., Cheng, A.L., El-Khoueiry, A.B., Rimassa, L., Ryoo, B.Y., Cicin, I., Merle, P., Chen, Y., Park, J.W., et al. (2018). Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54-63. https://doi.org/10.1056/NEJMoa1717002
  2. Albert, M. and Helin, K. (2010). Histone methyltransferases in cancer. Semin. Cell Dev. Biol. 21, 209-220. https://doi.org/10.1016/j.semcdb.2009.10.007
  3. Brown, R., Curry, E., Magnani, L., Wilhelm-Benartzi, C.S., and Borley, J. (2014). Poised epigenetic states and acquired drug resistance in cancer. Nat. Rev. Cancer 14, 747-753. https://doi.org/10.1038/nrc3819
  4. Bruix, J., Qin, S., Merle, P., Granito, A., Huang, Y.H., Bodoky, G., Pracht, M., Yokosuka, O., Rosmorduc, O., Breder, V., et al. (2017). Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56-66. https://doi.org/10.1016/S0140-6736(16)32453-9
  5. Cao, X., Ding, Q., Lu, J., Tao, W., Huang, B., Zhao, Y., Niu, J., Liu, Y.J., and Zhong, J. (2015). MDA5 plays a critical role in interferon response during hepatitis C virus infection. J. Hepatol. 62, 771-778. https://doi.org/10.1016/j.jhep.2014.11.007
  6. Chen, Z., Xie, H., Hu, M., Huang, T., Hu, Y., Sang, N., and Zhao, Y. (2020). Recent progress in treatment of hepatocellular carcinoma. Am. J. Cancer Res. 10, 2993-3036.
  7. Cheng, Y., He, C., Wang, M., Ma, X., Mo, F., Yang, S., Han, J., and Wei, X. (2019). Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct. Target. Ther. 4, 62.
  8. de Lope, C.R., Tremosini, S., Forner, A., Reig, M., and Bruix, J. (2012). Management of HCC. J. Hepatol. 56 Suppl 1, S75-S87.
  9. Deliu, E., Arecco, N., Morandell, J., Dotter, C.P., Contreras, X., Girardot, C., Kasper, E.L., Kozlova, A., Kishi, K., Chiaradia, I., et al. (2018). Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nat. Neurosci. 21, 1717-1727. https://doi.org/10.1038/s41593-018-0266-2
  10. Dillon, S.C., Zhang, X., Trievel, R.C., and Cheng, X. (2005). The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 6, 227.
  11. Dobin, A., Davis, C.A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., and Gingeras, T.R. (2013). STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15-21. https://doi.org/10.1093/bioinformatics/bts635
  12. Feng, G.S., Hanley, K.L., Liang, Y., and Lin, X. (2021). Improving the efficacy of liver cancer immunotherapy: the power of combined preclinical and clinical studies. Hepatology 73 Suppl 1, 104-114.
  13. Fernandes, I.R., Cruz, A.C.P., Ferrasa, A., Phan, D., Herai, R.H., and Muotri, A.R. (2018). Genetic variations on SETD5 underlying autistic conditions. Dev. Neurobiol. 78, 500-518. https://doi.org/10.1002/dneu.22584
  14. Grivennikov, S.I., Greten, F.R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell 140, 883-899. https://doi.org/10.1016/j.cell.2010.01.025
  15. Howe, E.A., Sinha, R., Schlauch, D., and Quackenbush, J. (2011). RNA-Seq analysis in MeV. Bioinformatics 27, 3209-3210. https://doi.org/10.1093/bioinformatics/btr490
  16. Jeon, J., McGinty, R.K., Muir, T.W., Kim, J.A., and Kim, J. (2018). Crosstalk among Set1 complex subunits involved in H2B ubiquitylation-dependent H3K4 methylation. Nucleic Acids Res. 46, 11129-11143. https://doi.org/10.1093/nar/gky920
  17. Ji, J. and Wang, X.W. (2012). Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin. Oncol. 39, 461-472. https://doi.org/10.1053/j.seminoncol.2012.05.011
  18. Jones, P.A., Issa, J.P., and Baylin, S. (2016). Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630-641. https://doi.org/10.1038/nrg.2016.93
  19. Kim, I.K., McCutcheon, J.N., Rao, G., Liu, S.V., Pommier, Y., Skrzypski, M., Zhang, Y.W., and Giaccone, G. (2019). Acquired SETD2 mutation and impaired CREB1 activation confer cisplatin resistance in metastatic non-small cell lung cancer. Oncogene 38, 180-193. https://doi.org/10.1038/s41388-018-0429-3
  20. Kim, K.H. and Roberts, C.W. (2016). Targeting EZH2 in cancer. Nat. Med. 22, 128-134. https://doi.org/10.1038/nm.4036
  21. Kudo, M., Finn, R.S., Qin, S., Han, K.H., Ikeda, K., Piscaglia, F., Baron, A., Park, J.W., Han, G., Jassem, J., et al. (2018). Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163-1173. https://doi.org/10.1016/S0140-6736(18)30207-1
  22. Kwon, M., Park, K., Hyun, K., Lee, J.H., Zhou, L., Cho, Y.W., Ge, K., Skalnik, D.G., Muir, T.W., and Kim, J. (2020). H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes. Nucleic Acids Res. 48, 5442-5456. https://doi.org/10.1093/nar/gkaa317
  23. Lee, J.H., Tate, C.M., You, J.S., and Skalnik, D.G. (2007). Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. J. Biol. Chem. 282, 13419-13428. https://doi.org/10.1074/jbc.M609809200
  24. Liedtke, M. and Cleary, M.L. (2009). Therapeutic targeting of MLL. Blood 113, 6061-6068. https://doi.org/10.1182/blood-2008-12-197061
  25. Llovet, J.M., Kelley, R.K., Villanueva, A., Singal, A.G., Pikarsky, E., Roayaie, S., Lencioni, R., Koike, K., Zucman-Rossi, J., and Finn, R.S. (2021). Hepatocellular carcinoma. Nat. Rev. Dis. Primers 7, 6.
  26. Llovet, J.M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.F., de Oliveira, A.C., Santoro, A., Raoul, J.L., Forner, A., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378-390. https://doi.org/10.1056/NEJMoa0708857
  27. Lu, C., Klement, J.D., Yang, D., Albers, T., Lebedyeva, I.O., Waller, J.L., and Liu, K. (2020). SUV39H1 regulates human colon carcinoma apoptosis and cell cycle to promote tumor growth. Cancer Lett. 476, 87-96. https://doi.org/10.1016/j.canlet.2020.02.004
  28. Martin-Hijano, L. and Sainz, B., Jr. (2020). The interactions between cancer stem cells and the innate interferon signaling pathway. Front. Immunol. 11, 526.
  29. McCarthy, D.J., Chen, Y., and Smyth, G.K. (2012). Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 40, 4288-4297. https://doi.org/10.1093/nar/gks042
  30. Miyashita, M., Oshiumi, H., Matsumoto, M., and Seya, T. (2011). DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling. Mol. Cell. Biol. 31, 3802-3819. https://doi.org/10.1128/MCB.01368-10
  31. Moore, S.M., Seidman, J.S., Ellegood, J., Gao, R., Savchenko, A., Troutman, T.D., Abe, Y., Stender, J., Lee, D., Wang, S., et al. (2019). Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice. Transl. Psychiatry 9, 24.
  32. Oshiumi, H., Miyashita, M., Okamoto, M., Morioka, Y., Okabe, M., Matsumoto, M., and Seya, T. (2015). DDX60 is involved in RIG-I-dependent and independent antiviral responses, and its function is attenuated by virus-induced EGFR activation. Cell Rep. 11, 1193-1207. https://doi.org/10.1016/j.celrep.2015.04.047
  33. Osipovich, A.B., Gangula, R., Vianna, P.G., and Magnuson, M.A. (2016). Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation. Development 143, 4595-4607.
  34. Piao, L., Li, H., Feng, Y., Yang, Z., Kim, S., and Xuan, Y. (2020). SET domain-containing 5 is a potential prognostic biomarker that promotes esophageal squamous cell carcinoma stemness. Exp. Cell Res. 389 , 111861.
  35. Pietras, E.M., Lakshminarasimhan, R., Techner, J.M., Fong, S., Flach, J., Binnewies, M., and Passegue, E. (2014). Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J. Exp. Med. 211, 245-262. https://doi.org/10.1084/jem.20131043
  36. Qiu, Z., Li, H., Zhang, Z., Zhu, Z., He, S., Wang, X., Wang, P., Qin, J., Zhuang, L., Wang, W., et al. (2019). A pharmacogenomic landscape in human liver cancers. Cancer Cell 36, 179-193.e11. https://doi.org/10.1016/j.ccell.2019.07.001
  37. Reikine, S., Nguyen, J.B., and Modis, Y. (2014). Pattern recognition and signaling mechanisms of RIG-I and MDA5. Front. Immunol. 5, 342.
  38. Saung, M.T., Pelosof, L., Casak, S., Donoghue, M., Lemery, S., Yuan, M., Rodriguez, L., Schotland, P., Chuk, M., Davis, G., et al. (2021). FDA approval summary: nivolumab plus ipilimumab for the treatment of patients with hepatocellular carcinoma previously treated with sorafenib. Oncologist 26, 797-806. https://doi.org/10.1002/onco.13819
  39. Sessa, A., Fagnocchi, L., Mastrototaro, G., Massimino, L., Zaghi, M., Indrigo, M., Cattaneo, S., Martini, D., Gabellini, C., Pucci, C., et al. (2019). SETD5 regulates chromatin methylation state and preserves global transcriptional fidelity during brain development and neuronal wiring. Neuron 104, 271-289.e13. https://doi.org/10.1016/j.neuron.2019.07.013
  40. Shechter, D., Dormann, H.L., Allis, C.D., and Hake, S.B. (2007). Extraction, purification and analysis of histones. Nat. Protoc. 2, 1445-1457. https://doi.org/10.1038/nprot.2007.202
  41. Shen, H. and Laird, P.W. (2013). Interplay between the cancer genome and epigenome. Cell 153, 38-55. https://doi.org/10.1016/j.cell.2013.03.008
  42. Siegel, R.L., Miller, K.D., and Jemal, A. (2018). Cancer statistics, 2018. CA Cancer J. Clin. 68, 7-30. https://doi.org/10.3322/caac.21442
  43. Sowalsky, A.G., Xia, Z., Wang, L., Zhao, H., Chen, S., Bubley, G.J., Balk, S.P., and Li, W. (2015). Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol. Cancer Res. 13, 98-106. https://doi.org/10.1158/1541-7786.MCR-14-0273
  44. Tang, Z., Kang, B., Li, C., Chen, T., and Zhang, Z. (2019). GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 47(W1), W556-W560. https://doi.org/10.1093/nar/gkz430
  45. Uhlen, M., Zhang, C., Lee, S., Sjostedt, E., Fagerberg, L., Bidkhori, G., Benfeitas, R., Arif, M., Liu, Z., Edfors, F., et al. (2017). A pathology atlas of the human cancer transcriptome. Science 357, eaan2507.
  46. Vougiouklakis, T., Bernard, B.J., Nigam, N., Burkitt, K., Nakamura, Y., and Saloura, V. (2020). Clinicopathologic significance of protein lysine methyltransferases in cancer. Clin. Epigenetics 12, 146.
  47. Wang, Z., Hausmann, S., Lyu, R., Li, T.M., Lofgren, S.M., Flores, N.M., Fuentes, M.E., Caporicci, M., Yang, Z., Meiners, M.J., et al. (2020). SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy. Cancer Cell 37, 834-849.e13. https://doi.org/10.1016/j.ccell.2020.04.014
  48. Worns, M.A. and Galle, P.R. (2010). Future perspectives in hepatocellular carcinoma. Dig. Liver Dis. 42 Suppl 3, S302-S309. https://doi.org/10.1016/S1590-8658(10)60521-X
  49. Yang, Z., Zhang, C., Che, N., Feng, Y., Li, C., and Xuan, Y. (2021). Su(var)3-9, Enhancer of zeste, and Trithorax domain-containing 5 facilitates tumor growth and pulmonary metastasis through up-regulation of AKT1 signaling in breast cancer. Am. J. Pathol. 191, 180-193. https://doi.org/10.1016/j.ajpath.2020.10.005
  50. Yu, H., Sun, J., Zhao, C., Wang, H., Liu, Y., Xiong, J., Chang, J., Wang, M., Wang, W., Ye, D., et al. (2019). SET domain containing protein 5 (SETD5) enhances tumor cell invasion and is associated with a poor prognosis in non-small cell lung cancer patients. BMC Cancer 19, 736.