The Oncogenic Role of Holliday Junction Recognition Protein in Hepatocellular Carcinoma

Year 2025, Volume: 42 Issue: 1, 69 - 79, 28.03.2025

Melek Yuce , Esra Albayrak , İlayda Şişli

Abstract

The relationship between centromere dysfunction leading to numerical chromosomal changes and cancer is well-known. The chaperone of the centromere-specific protein Centromere Protein A (CENP-A), known as Holliday Junction Recognition Protein (HJURP), is considered a crucial factor in the establishment of centromere identity. The researches have shown that CENP-A is overexpressed in many types of human cancers. However, the behavior and function of HJURP in tumorigenesis have only recently been elucidated. In this review, the relationship between hjurp and liver cancer and its role in cancer development has been summarized.

Keywords

Chaperone, HJURP, CENP-A, liver cancer, hepatocellular carcinoma, prognosis

Ethical Statement

None to declare.

Supporting Institution

None to declare.

Thanks

None to declare.

References

• 1. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):1-28.
• 2. Balogh J, Victor III D, Asham EH, Burroughs SG, Boktour M, Saharia A, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016:41-53.
• 3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
• 4. Grandhi MS, Kim AK, Ronnekleiv-Kelly SM, Kamel IR, Ghasebeh MA, Pawlik TM. Hepatocellular carcinoma: from diagnosis to treatment. Surg Oncol. 2016;25(2):74-85.
• 5. Bangaru S, Marrero JA, Singal AG. New therapeutic interventions for advanced hepatocellular carcinoma. Aliment Pharmacol Ther. 2020;51(1):78-89.
• 6. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604.
• 7. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674-87.
• 8. Levine MS, Holland AJ. The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev. 2018;32(9-10):620-38.
• 9. Tanaka K, Hirota T. Chromosomal instability: A common feature and a therapeutic target of cancer. Biochim Biophys Acta Rev Cancer. 2016;1866(1):64-75.
• 10. Daher S, Massarwa M, Benson AA, Khoury T. Current and future treatment of hepatocellular carcinoma: an updated comprehensive review. J Clin Transl Hepatol. 2018;6(1):69.
• 11. Ho DW-H, Lo RC-L, Chan L-K, Ng IO-L. Molecular pathogenesis of hepatocellular carcinoma. Liver Cancer. 2016;5(4):290-302.
• 12. Villanueva A, Hoshida Y. Depicting the role of TP53 in hepatocellular carcinoma progression. J Hepatol. 2011;55(3):724-5.
• 13. Shrestha RL, Ahn GS, Staples MI, Sathyan KM, Karpova TS, Foltz DR, et al. Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. Oncotarget. 2017;8(29):46781.
• 14. Arimura Y, Shirayama K, Horikoshi N, Fujita R, Taguchi H, Kagawa W, et al. Crystal structure and stable property of the cancer-associated heterotypic nucleosome containing CENP-A and H3.3. Sci Rep. 2014;4(1):7115.
• 15. Li Y, Zhu Z, Zhang S, Yu D, Yu H, Liu L, et al. ShRNA-targeted centromere protein A inhibits hepatocellular carcinoma growth. PLoS One. 2011;6(3):e17794.
• 16. Foltz DR, Jansen LE, Bailey AO, Yates JR, Bassett EA, Wood S, et al. Centromere-specific assembly of CENP-A nucleosomes is mediated by HJURP. Cell. 2009;137(3):472-84.
• 17. Dunleavy EM, Roche D, Tagami H, Lacoste N, Ray-Gallet D, Nakamura Y, et al. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell. 2009;137(3):485-97.
• 18. Mahlke MA, Nechemia-Arbely Y. Guarding the genome: CENP-A-chromatin in health and cancer. Genes (Basel). 2020;11(7):810.
• 19. Winkler DD, Luger K. The histone chaperone FACT: structural insights and mechanisms for nucleosome reorganization. J Biol Chem. 2011;286(21):18369-74.
• 20. Tyler JK. Chromatin assembly: Cooperation between histone chaperones and ATP‐dependent nucleosome remodeling machines. Eur J Biochem. 2002;269(9):2268-74.
• Elbette, referanslarınızı belirttiğiniz gibi düzenleyelim:
• 21. Gurard-Levin ZA, Quivy J-P, Almouzni G. Histone chaperones: assisting histone traffic and nucleosome dynamics. Annu Rev Biochem. 2014;83(1):487-517.
• 22. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature. 1997;389(6648):251-60.
• 23. Warren C, Shechter D. Fly fishing for histones: catch and release by histone chaperone intrinsically disordered regions and acidic stretches. J Mol Biol. 2017;429(16):2401-26.
• 24. Groth A, Rocha W, Verreault A, Almouzni G. Chromatin challenges during DNA replication and repair. Cell. 2007;128(4):721-33.
• 25. Ransom M, Dennehey BK, Tyler JK. Chaperoning histones during DNA replication and repair. Cell. 2010;140(2):183-95.
• 26. Hondele M, Ladurner AG. The chaperone–histone partnership: for the greater good of histone traffic and chromatin plasticity. Curr Opin Struct Biol. 2011;21(6):698-708.
• 27. Laskey R, Honda B, Mills A, Finch J. Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature. 1978;275(5679):416-20.
• 28. Talbert PB, Henikoff S. Histone variants on the move: substrates for chromatin dynamics. Nat Rev Mol Cell Biol. 2017;18(2):115-26.
• 29. Akey CW, Luger K. Histone chaperones and nucleosome assembly. Curr Opin Struct Biol. 2003;13(1):6-14.
• 30. Venkatesh S, Workman JL. Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol. 2015;16(3):178-89.
• 31. Burgess RJ, Zhang Z. Histone chaperones in nucleosome assembly and human disease. Nat Struct Mol Biol. 2013;20(1):14-22.
• 32. Wang C-J, Li X, Shi P, Ding H-Y, Liu Y-P, Li T, et al. Holliday junction recognition protein promotes pancreatic cancer growth and metastasis via modulation of the MDM2/p53 signaling. Cell Death Dis. 2020;11(5):386.
• 33. de Oca RM, Gurard-Levin ZA, Berger F, Rehman H, Martel E, Corpet A, et al. The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma. Mol Oncol. 2015;9(3):657-74.
• 34. Allu PK, Dawicki-McKenna JM, Van Eeuwen T, Slavin M, Braitbard M, Xu C, et al. Structure of the human core centromeric nucleosome complex. Curr Biol. 2019;29(16):2625-39.e5.
• 35. Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol. 2009;10(7):478-87.
• 36. Geigl JB, Obenauf AC, Schwarzbraun T, Speicher MR. Defining ‘chromosomal instability’. Trends Genet. 2008;24(2):64-9.
• 37. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463(7283):899-905.
• 38. Zhang W, Mao J-H, Zhu W, Jain AK, Liu K, Brown JB, et al. Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy. Nat Commun. 2016;7(1):12619.
• 39. Kixmoeller K, Allu PK, Black BE. The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle. Open Biol. 2020;10(6):200051.
• 40. Hu Z, Huang G, Sadanandam A, Gu S, Lenburg ME, Pai M, et al. The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer. Breast Cancer Res. 2010;12(2):R18.
• 41. Cheeseman IM. The kinetochore. Cold Spring Harb Perspect Biol. 2014;6(7):a015826.
• 42. Swartz SZ, McKay LS, Su K-C, Bury L, Padeganeh A, Maddox PS, et al. Quiescent cells actively replenish CENP-A nucleosomes to maintain centromere identity and proliferative potential. Dev Cell. 2019;51(1):35-48.e7.
• 43. Mellone BG, Allshire RC. Stretching it: putting the CEN (PA) in centromere. Curr Opin Genet Dev. 2003;13(2):191-8.
• 44. Maehara K, Takahashi K, Saitoh S. CENP-A reduction induces a p53-dependent cellular senescence response to protect cells from executing defective mitoses. Mol Cell Biol. 2010.
• 45. Sharma AB, Dimitrov S, Hamiche A, Van Dyck E. Centromeric and ectopic assembly of CENP-A chromatin in health and cancer: old marks and new tracks. Nucleic Acids Res. 2019;47(3):1051-69.
• Elbette, referanslarınızı belirttiğiniz gibi düzenleyelim:
• 46. Stellfox ME, Bailey AO, Foltz DR. Putting CENP-A in its place. Cell Mol Life Sci. 2013;70:387-406.
• 47. Amaro AC, Samora CP, Holtackers R, Wang E, Kingston IJ, Alonso M, et al. Molecular control of kinetochore-microtubule dynamics and chromosome oscillations. Nat Cell Biol. 2010;12(4):319-29.
• 48. Sen S. Aneuploidy and cancer. Curr Opin Oncol. 2000;12(1):82-8.
• 49. Sansregret L, Swanton C. The role of aneuploidy in cancer evolution. Cold Spring Harb Perspect Med. 2017;7(1):a028373.
• 50. Tahmasebi-Birgani M, Ansari H, Carloni V. Defective mitosis-linked DNA damage response and chromosomal instability in liver cancer. Biochim Biophys Acta Rev Cancer. 2019;1872(1):60-5.
• 51. Wilkens L, Flemming P, Gebel M, Bleck J, Terkamp C, Wingen L, et al. Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2004;101(5):1309-14.
• 52. Molina O, Abad MA, Solé F, Menéndez P. Aneuploidy in cancer: lessons from acute lymphoblastic leukemia. Trends Cancer. 2021;7(1):37-47.
• 53. Tomonaga T, Matsushita K, Yamaguchi S, Oohashi T, Shimada H, Ochiai T, et al. Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res. 2003;63(13):3511-6.
• 54. Amato A, Schillaci T, Lentini L, Di Leonardo A. CENPA overexpression promotes genome instability in pRb-depleted human cells. Mol Cancer. 2009;8:1-14.
• 55. Wu Q, Chen Y-F, Fu J, You Q-H, Wang S-M, Huang X, et al. Short hairpin RNA-mediated down-regulation of CENP-A attenuates the aggressive phenotype of lung adenocarcinoma cells. Cell Oncol (Dordr). 2014;37:399-407.
• 56. Wu Q, Qian Y-M, Zhao X-L, Wang S-M, Feng X-J, Chen X-F, et al. Expression and prognostic significance of centromere protein A in human lung adenocarcinoma. Lung Cancer. 2012;77(2):407-14.
• 57. Bieniek J, Childress C, Swatski MD, Yang W. COX‐2 inhibitors arrest prostate cancer cell cycle progression by down‐regulation of kinetochore/centromere proteins. Prostate. 2014;74(10):999-1011.
• 58. Qiu J-J, Guo J-J, Lv T-J, Jin H-Y, Ding J-X, Feng W-W, et al. Prognostic value of centromere protein-A expression in patients with epithelial ovarian cancer. Tumour Biol. 2013;34:2971-5.
• 59. McGovern SL, Qi Y, Pusztai L, Symmans WF, Buchholz TA. Centromere protein-A, an essential centromere protein, is a prognostic marker for relapse in estrogen receptor-positive breast cancer. Breast Cancer Res. 2012;14:1-11.
• 60. Li Y, Liu X, Cao X, Wang L, Zhu M. Expression of centromere protein A in hepatocellular carcinoma. Zhonghua Bing Li Xue Za Zhi. 2007;36(3):175-8.
• 61. Zhang Y, Yang L, Shi J, Lu Y, Chen X, Yang Z. The oncogenic role of CENPA in hepatocellular carcinoma development: evidence from bioinformatic analysis. Biomed Res Int. 2020;2020(1):3040839.
• 62. Liao J, Chen Z, Chang R, Yuan T, Li G, Zhu C, et al. CENPA functions as a transcriptional regulator to promote hepatocellular carcinoma progression via cooperating with YY1. Int J Biol Sci. 2023;19(16):5218.
• 63. Liang D, Luo L, Wang J, Liu T, Guo C. CENPA-driven STMN1 transcription inhibits ferroptosis in hepatocellular carcinoma. J Clin Transl Hepatol. 2023;11(5):1118.
• 64. Liu L, Li Y, Zhang S, Yu D, Zhu M. Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells. Oncol Rep. 2012;27(1):168-73.
• 65. Ghiraldini FG, Filipescu D, Bernstein E. Solid tumours hijack the histone variant network. Nat Rev Cancer. 2021;21(4):257-75.
• 66. Hu B, Wang Q, Wang Y, Chen J, Li P, Han M. Holliday junction–recognizing protein promotes cell proliferation and correlates with unfavorable clinical outcome of hepatocellular carcinoma. Onco Targets Ther. 2017:2601-7.
• 67. Mishra PK, Au WC, Choy JS, Kuich PH, Baker RE, Foltz DR, et al. Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells. PLoS Genet. 2011;7(9):e1002303.
• 68. Kato T, Sato N, Hayama S, Yamabuki T, Ito T, Miyamoto M, et al. Activation of holliday junction–recognizing protein involved in the chromosomal stability and immortality of cancer cells. Cancer Res. 2007;67(18):8544-53.
• 69. Kang DH, Woo J, Kim H, Kim SY, Ji S, Jaygal G, et al. Prognostic relevance of HJURP expression in patients with surgically resected colorectal cancer. Int J Mol Sci. 2020;21(21):7928.
• 70. Serafim RB, Cardoso C, Di Cristofaro LF, Pienna Soares C, Araújo Silva Jr W, Espreafico EM, et al. HJURP knockdown disrupts clonogenic capacity and increases radiation-induced cell death of glioblastoma cells. Cancer Gene Ther. 2020;27(5):319-29.
• 71. Li Y, Yi Q, Liao X, Han C, Zheng L, Li H, et al. Hypomethylation-driven overexpression of HJURP promotes progression of hepatocellular carcinoma and is associated with poor prognosis. Biochem Biophys Res Commun. 2021;566:67-74.
• 72. Luo D, Liao S, Liu Y, Lin Y, Li Y, Liao X. Holliday cross-recognition protein HJURP: association with the tumor microenvironment in hepatocellular carcinoma and with patient prognosis. Pathol Oncol Res. 2022;28:1610506.
• 73. Huang W, Zhang H, Hao Y, Xu X, Zhai Y, Wang S, et al. A non-synonymous single nucleotide polymorphism in the HJURP gene associated with susceptibility to hepatocellular carcinoma among Chinese. PLoS One. 2016;11(2):e0148618.
• 74. Liu Y, Liu S, Jing R, Li C, Guo Y, Cai Z, et al. Identification of ASF1A and HJURP by global H3–H4 histone chaperone analysis as a prognostic two-gene model in hepatocellular carcinoma. Sci Rep. 2024;14(1):7666.
• 75. Chen T, Huang H, Zhou Y, Geng L, Shen T, Yin S, et al. HJURP promotes hepatocellular carcinoma proliferation by destabilizing p21 via the MAPK/ERK1/2 and AKT/GSK3β signaling pathways. J Exp Clin Cancer Res. 2018;37:1-14.
• 76. Chen T, Zhou L, Zhou Y, Zhou W, Huang H, Yin S, et al. HJURP promotes epithelial-to-mesenchymal transition via upregulating SPHK1 in hepatocellular carcinoma. Int J Biol Sci. 2019;15(6):1139.
• Elbette, referanslarınızı belirttiğiniz gibi düzenleyelim:
• 77. Cao R, Wang G, Qian K, Chen L, Qian G, Xie C, et al. Silencing of HJURP induces dysregulation of cell cycle and ROS metabolism in bladder cancer cells via PPARγ-SIRT1 feedback loop. J Cancer. 2017;8(12):2282.
• 78. Wei Y, Ouyang G-L, Yao W-X, Zhu Y-J, Li X, Huang L-X, et al. Knockdown of HJURP inhibits non-small cell lung cancer cell proliferation, migration, and invasion by repressing Wnt/β-catenin signaling. Eur Rev Med Pharmacol Sci. 2019;23(9).
• 79. de Tayrac M, Saikali S, Aubry M, Bellaud P, Boniface R, Quillien V, et al. Prognostic significance of EDN/RB, HJURP, p60/CAF-1 and PDLI4, four new markers in high-grade gliomas. PLoS One. 2013;8(9):e73332.
• 80. Valente V, Serafim RB, de Oliveira LC, Adorni FS, Torrieri R, da Cunha Tirapelli DP, et al. Modulation of HJURP (Holliday Junction-Recognizing Protein) levels is correlated with glioblastoma cells survival. PLoS One. 2013;8(4):e62200.
• 81. Li L, Li X, Meng Q, Khan AQ, Chen X. Increased expression of Holliday junction-recognizing protein (HJURP) as an independent prognostic biomarker in advanced-stage serous ovarian carcinoma. Med Sci Monit. 2018;24:3050.
• 82. Chen Y-F, Liang Y-X, Yang J-A, Yuan D-Z, Li J, Zheng S-S, et al. Upregulation of Holliday junction recognition protein predicts poor prognosis and biochemical recurrence in patients with prostate cancer. Oncol Lett. 2019;18(6):6697-703.
• 83. Yuan J-S, Chen Z-S, Wang K, Zhang Z-L. Holliday junction-recognition protein modulates apoptosis, cell cycle arrest and reactive oxygen species stress in human renal cell carcinoma. Oncol Rep. 2020;44(3):1246-54.
• 84. Shen KC, Heng H, Wang Y, Lu S, Liu G, Deng C-X, et al. ATM and p21 cooperate to suppress aneuploidy and subsequent tumor development. Cancer Res. 2005;65(19):8747-53.
• 85. Ohkoshi S, Yano M, Matsuda Y. Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy. World J Gastroenterol. 2015;21(42):12150.
• 86. Shen S, Dean DC, Yu Z, Duan Z. Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway. Hepatol Res. 2019;49(10):1097-108.
• 87. Leal-Esteban LC, Fajas L. Cell cycle regulators in cancer cell metabolism. Biochim Biophys Acta Mol Basis Dis. 2020;1866(5):165715.
• 88. Matsuda Y. Molecular mechanism underlying the functional loss of cyclin-dependent kinase inhibitors p16 and p27 in hepatocellular carcinoma. World J Gastroenterol. 2008;14(11):1734.
• 89. Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9(6):400-14.
• 90. Roche J. The epithelial-to-mesenchymal transition in cancer. Cancers (Basel). 2018;10(2):52.
• 91. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168(4):670-91.
• 92. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-96.
• 93. Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol. 2016;65(4):798-808.
• 94. Liu H, Ma Y, He H-W, Zhao W-L, Shao R-G. SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells. Autophagy. 2017;13(5):900-13.
• 95. Bao M, Chen Z, Xu Y, Zhao Y, Zha R, Huang S, et al. Sphingosine kinase 1 promotes tumour cell migration and invasion via the S1P/EDG 1 axis in hepatocellular carcinoma. Liver Int. 2012;32(2):331-8.
• 96. Fan Z, Jiang H, Wang Z, Qu J. Atorvastatin partially inhibits the epithelial-mesenchymal transition in A549 cells induced by TGF-β1 by attenuating the upregulation of SphK1. Oncol Rep. 2016;36(2):1016-22.
• 97. Xu C-Y, Liu S-Q, Qin M-B, Zhuge C-F, Qin L, Qin N, et al. SphK1 modulates cell migration and EMT-related marker expression by regulating the expression of p-FAK in colorectal cancer cells. Int J Mol Med. 2017;39(5):1277-84.
• 98. Farazi PA, Glickman J, Horner J, DePinho RA. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 2006;66(9):4766-73.
• 99. Tornesello ML, Buonaguro L, Tatangelo F, Botti G, Izzo F, Buonaguro FM. Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics. 2013;102(2):74-83.
• 100. Hsu I, Metcalf R, Sun T, Welsh J, Wang N, Harris C. Mutational hot spot in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350(6317):427-8.
• 101. Hussain S, Schwank J, Staib F, Wang X, Harris C. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26(15):2166-76.
• 102. Wang XW, Hussain SP, Huo T-I, Wu C-G, Forgues M, Hofseth LJ, et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology. 2002;181:43-7.
• 103. Nault J-C. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol. 2014;28(5):937-47.
• 104. Filipescu D, Naughtin M, Podsypanina K, Lejour V, Wilson L, Gurard-Levin ZA, et al. Essential role for centromeric factors following p53 loss and oncogenic transformation. Genes Dev. 2017;31(5):463-80.
• 105. Dermawan JKT, Hitomi M, Silver DJ, Wu Q, Sandlesh P, Sloan AE, et al. Pharmacological targeting of the histone chaperone complex FACT preferentially eliminates glioblastoma stem cells and prolongs survival in preclinical models. Cancer Res. 2016;76(8):2432-42.