Экспрессия и биологическая роль YY1 в репродуктивной системе человека

Транскрипционный фактор Yin Yang 1 (YY1) представляет собой многофункциональный регулятор экспрессии генов, участвующий в широком спектре физиологических и патологических процессов. В последние годы все большее внимание уделяется его роли в репродуктивной системе человека, однако данные остаются разрозненными и требуют систематизации. Настоящий обзор обобщает современные экспериментальные и клинические сведения об экспрессии и биологической функции YY1 в женской и мужской репродуктивной системе. В женской репродуктивной системе YY1 участвует в регуляции фолликулогенеза и созревания ооцита, раннего эмбрионального развития, имплантации и процессов плацентации. Показано его влияние на инвазивные и иммуномодулирующие свойства трофобласта, а также на формирование маточно-плацентарного интерфейса. Нарушения экспрессии YY1 ассоциированы с такими гестационными осложнениями, как привычное невынашивание беременности и преэклампсия. Отдельный раздел обзора посвящен роли YY1 в патогенезе гинекологических злокачественных новообразований, включая рак яичников, рак шейки матки и рак эндометрия, где YY1 вовлечен в регуляцию опухолевого роста, инвазии, стволовых свойств опухолевых клеток и чувствительности к противоопухолевой терапии. В мужской репродуктивной системе YY1 играет ключевую роль в сперматогенезе, поддержании функции сперматогониальных стволовых клеток и мейотическом делении. Кроме того, показано его участие в молекулярных механизмах прогрессирования рака предстательной железы и формировании устойчивости опухолевых клеток к апоптозу и лекарственному воздействию. YY1 является важным узловым регулятором репродуктивных процессов в норме и патологии. Дальнейшее изучение молекулярных механизмов его действия может способствовать разработке новых диагностических маркеров и таргетных терапевтических подходов в репродуктологии и онкогинекологии.

1. Martins Peçanha F.L., Jaafar R., Werneck-de-Castro J.P. et al. The transcription factor YY1 is essential for normal DNA repair and cell cycle in human and mouse β-cells. Diabetes. 2022;71(8):1694–705. https://doi.org/10.2337/db21-0908.

2. Huang N.E., Lin C.H., Lin Y.S., Yu W.C. Modulation of YY1 activity by SAP30. Biochem Biophys Res Commun. 2003;306(1):267–75. https://doi.org/10.1016/S0006-291X(03)00966-5.

3. Khachigian L.M. The Yin and Yang of YY1 in tumor growth and suppression. Int J Cancer. 2018;143(3):460–465. https://doi.org/10.1002/ijc.31255.

4. Houbaviy H.B., Usheva A., Shenk T. et al. Cocrystal structure of YY1 bound to the adeno-associated virus P5 initiator. Proc Natl Acad Sci U S A. 1996;93(24):13577–82. https://doi.org/10.1073/pnas.93.24.13577.

5. Donald H., Blane A., Buthelezi S. et al. Assessing the dynamics and macromolecular interactions of the intrinsically disordered protein YY1. Biosci Rep. 2023;43(10):BSR20231295. https://doi.org/10.1042/BSR20231295.

6. Feng L., Ma Y., Sun J. et al. YY1–MIR372–SQSTM1 regulatory axis in autophagy. Autophagy. 2014;10(8):1442–53. https://doi.org/10.4161/auto.29486.

7. Wang X., Fan W., Li N. et al. YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2. Genome Biol. 2023;24(1):87. https://doi.org/10.1186/s13059-023-02931-y.

8. Kleiman E., Jia H., Loguercio S. et al. YY1 plays an essential role at all stages of B-cell differentiation. Proc Natl Acad Sci U S A. 2016;113(27):E3911–E3920. https://doi.org/10.1073/pnas.1606297113.

9. Hwang S.S., Jang S.W., Kim M.K. et al. YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity. Nat Commun. 2016;7:10789. https://doi.org/10.1038/ncomms10789.

10. Chen F., Zhou J., Li Y. et al. YY1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells. EMBO J. 2019;38(10):e99727. https://doi.org/10.15252/embj.201899727.

11. Meliala I.T.S., Hosea R., Kasim V., Wu S. The biological implications of Yin Yang 1 in the hallmarks of cancer. Theranostics. 2020;10(9):4183–200. https://doi.org/10.7150/thno.43481.

12. Lichtenauer U.D., Di Dalmazi G., Slater E.P. et al. Frequency and clinical correlates of somatic Yin Yang 1 mutations in sporadic insulinomas. J Clin Endocrinol Metab. 2015;100(5):E776–E782. https://doi.org/10.1210/jc.2015-1100.

13. Cao Y., Gao Z., Li L. et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun. 2013;4:2810. https://doi.org/10.1038/ncomms3810.

14. Figiel M., Łakomska J., Dziedzicka-Wasylewska M., Górecki A. The effect of D380Y pathogenic mutation in human Yin Yang 1 on the protein's structure and function. Acta Biochim Pol. 2020;67(1):73–7. https://doi.org/10.18388/abp.2020_2911.

15. Zurkirchen L., Varum S., Giger S. et al. Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner. Nat Commun. 2019;10(1):2192. https://doi.org/10.1038/s41467-019-09823-5.

16. Tian F.J., Cheng Y.X., Li X.C. et al. The YY1/MMP2 axis promotes trophoblast invasion at the maternal–fetal interface. J Pathol. 2016;239(1):36–47. https://doi.org/10.1002/path.4694.

17. Yang D., Ding J., Wang Y. et al. YY1–PVT1 affects trophoblast invasion and adhesion by regulating mTOR pathway-mediated autophagy. J Cell Physiol. 2020;235(10):6637–46. https://doi.org/10.1002/jcp.29560.

18. Ficzycz A., Eskiw C., Meyer D. et al. Expression, activity, and subcellular localization of the Yin Yang 1 transcription factor in Xenopus oocytes and embryos. J Biol Chem. 2001;276(25):22819–25. https://doi.org/10.1074/jbc.M011188200.

19. Griffith G.J., Trask M.C., Hiller J. et al. Yin Yang 1 is required in the mammalian oocyte for follicle expansion. Biol Reprod. 2011;84(4):654–63. https://doi.org/10.1095/biolreprod.110.087213.

20. Hu M., Gao T., Du Y. MiR-98-3p regulates ovarian granulosa cell proliferation and apoptosis in polycystic ovary syndrome by targeting YY1. Med Mol Morphol. 2022;55(1):47–59. https://doi.org/10.1007/s00795-021-00307-4.

21. Yin Y., Zhang J., Yu H. et al. Effect of lncRNA-ATB/miR-651-3p/Yin Yang 1 pathway on trophoblast–endothelial cell interaction networks. J Cell Mol Med. 2021;25(12):5391–403. https://doi.org/10.1111/jcmm.16550.

22. Morshed M., Ando M., Yamamoto J. et al. YY1 binds to regulatory element of chicken lysozyme and ovalbumin promoters. Cytotechnology. 2006;52(3):159–70. https://doi.org/10.1007/s10616-006-9017-4.

23. Li R., Song X.T., Guo S.W. et al. YY1 and RTCB in mouse uterine decidualization and embryo implantation. Reproduction. 2021;162(6):461–72. https://doi.org/10.1530/REP-21-0281.

24. Li H., Yu L., Ding Y. et al. Yin Yang 1 impacts upon preeclampsia by regulating Treg/Th17 cells and PI3K/AKT pathway. J Immunotoxicol. 2023;20(1):2228420. https://doi.org/10.1080/1547691X.2023.2228420.

25. Uhlén M., Fagerberg L., Hallström B.M. et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419.

26. Zhao H., Dong Y., Zhang Y. et al. Supplementation of SDF1 during pig oocyte in vitro maturation improves subsequent embryo development. Molecules. 2022;27(20):6830. https://doi.org/10.3390/molecules27206830.

27. Bunker C.A., Kingston R.E. Transcriptional repression by Drosophila and mammalian Polycomb group proteins in transfected mammalian cells. Mol Cell Biol. 1994;14(3):1721–32. https://doi.org/10.1128/mcb.14.3.1721-1732.1994.

28. Roy B., Lee A.S. The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res. 1999;27(6):1437–43. https://doi.org/10.1093/nar/27.6.1437.

29. Chen W., E Q., Sun B. et al. PARP1-catalyzed PARylation of YY1 mediates endoplasmic reticulum stress in granulosa cells to determine primordial follicle activation. Cell Death Dis. 2023;14(8):524. https://doi.org/10.1038/s41419-023-05984-w.

30. Du X., Guo J., Cao Q.Y. et al. A haplotype variant of Hu sheep follicle-stimulating hormone receptor promoter region decreases transcriptional activity. Anim Genet. 2019;50(4):407–11. https://doi.org/10.1111/age.12794.

31. Zhou M., Liu X., Qiukai E. et al. Long non-coding RNA Xist regulates oocyte loss via suppressing miR-23b-3p/miR-29a-3p maturation and upregulating STX17 in perinatal mouse ovaries. Cell Death Dis. 2021;12(6):540. https://doi.org/10.1038/s41419-021-03831-4.

32. Jin L., Yang Q., Zhou C. et al. Profiles for long non-coding RNAs in ovarian granulosa cells from women with PCOS with or without hyperandrogenism. Reprod Biomed Online. 2018;37(5):613–23. https://doi.org/10.1016/j.rbmo.2018.08.005.

33. Wallingford M.C., Hiller J., Zhang K., Mager J. YY1 is required for posttranscriptional stability of SOX2 and OCT4 proteins. Cell Reprogram. 2017;19(4):263–9. https://doi.org/10.1089/cell.2017.0002.

34. Wang T., Peng J., Fan J. et al. Single-cell multi-omics profiling of human preimplantation embryos identifies cytoskeletal defects during embryonic arrest. Nat Cell Biol. 2024;26(2):263–77. https://doi.org/10.1038/s41556-023-01328-0.

35. Sakamoto M., Abe S., Miki Y. et al. Dynamic nucleosome remodeling mediated by YY1 underlies early mouse development. Genes Dev. 2023;37(13–14):590–604. https://doi.org/10.1101/gad.350376.122.

36. Dong Y., Wu X., Peng X. et al. Knockdown of YY1 inhibits XIST expression and enhances cloned pig embryo development. Int J Mol Sci. 2022;23(23):14572. https://doi.org/10.3390/ijms232314572.

37. Donohoe M.E., Zhang X., McGinnis L. et al. Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol. 1999;19(10):7237–44. https://doi.org/10.1128/MCB.19.10.7237.

38. Staun-Ram E., Shalev E. Human trophoblast function during the implantation process. Reprod Biol Endocrinol. 2005;3:56. https://doi.org/10.1186/1477-7827-3-56.

39. Zhang X.Y., Qin X.Y., Shen H.H. et al. IL-27 deficiency inhibits proliferation and invasion of trophoblasts via the SFRP2/Wnt/β-catenin pathway in fetal growth restriction. Int J Med Sci. 2023;20(3):392–405. https://doi.org/10.7150/ijms.80684.

40. Jiang L., Long A., Tan L. et al. Elevated microRNA-520g in pre-eclampsia inhibits migration and invasion of trophoblasts. Placenta. 2017;51:70–5. https://doi.org/10.1016/j.placenta.2017.02.001.

41. Ding J., Zhang Y., Cai X. et al. Extracellular vesicles derived from M1 macrophages deliver miR-146a-5p and miR-146b-5p to suppress trophoblast migration and invasion by targeting TRAF6 in recurrent spontaneous abortion. Theranostics. 2021;11(12):5813–30. https://doi.org/10.7150/thno.58731.

42. Zhang Y., Wang H., Qiu P. et al. Decidual macrophages derived NO downregulates PD-L1 in trophoblasts leading to decreased Treg cells in recurrent miscarriage. Front Immunol. 2023;14:1180154. https://doi.org/10.3389/fimmu.2023.1180154.

43. Wang Y., Yang D., Zhu R. et al. YY1/ITGA3 pathway may affect trophoblastic cells migration and invasion ability. J Reprod Immunol. 2022;153:103666. https://doi.org/10.1016/j.jri.2022.103666.

44. Wang Y., Chen A. Mast cell-derived exosomal miR-181a-5p modulated trophoblast cell viability, migration, and invasion via YY1/MMP-9 axis. J Clin Lab Anal. 2022;36(7):e24549. https://doi.org/10.1002/jcla.24549.

45. Wang R., Su L., Yu S. et al. Inhibition of PHLDA2 transcription by DNA methylation and YY1 in goat placenta. Gene. 2020;739:144512. https://doi.org/10.1016/j.gene.2020.144512.

46. Mahadevan S., Wen S., Wan Y.W. et al. NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation. Hum Mol Genet. 2014;23(3):706–16. https://doi.org/10.1093/hmg/ddt457.

47. Arribas J., Castellví J., Marcos R. et al. Expression of YY1 in differentiated thyroid cancer. Endocr Pathol. 2015;26(2):111–8. https://doi.org/10.1007/s12022-015-9359-6.

48. Kaufhold S., Garbán H., Bonavida B. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res. 2016;35:84. https://doi.org/10.1186/s13046-016-0359-2.

49. Baritaki S., Sifakis S., Huerta-Yepez S. et al. Overexpression of VEGF and TGF-beta1 mRNA in Pap smears correlates with progression of cervical intraepithelial neoplasia to cancer: implication of YY1 in cervical tumorigenesis and HPV infection. Int J Oncol. 2007;31(1):69–79.

50. Wang W., Yue Z., Tian Z. et al. Expression of Yin Yang 1 in cervical cancer and its correlation with E-cadherin expression and HPV16 E6. PLoS One. 2018;13(2):e0193340. https://doi.org/10.1371/journal.pone.0193340.

51. He G., Wang Q., Zhou Y. et al. YY1 is a novel potential therapeutic target for the treatment of HPV infection-induced cervical cancer by arsenic trioxide. Int J Gynecol Cancer. 2011;21(6):1097–104. https://doi.org/10.1097/IGC.0b013e31821d2525.

52. Zhou W.Y., Chen J.C., Jiao T.T. et al. MicroRNA-181 targets Yin Yang 1 expression and inhibits cervical cancer progression. Mol Med Rep. 2015;11(6):4541–6. https://doi.org/10.3892/mmr.2015.3324.

53. Liu H., Xu J., Yang Y. et al. Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1. Proc Natl Acad Sci U S A. 2021;118(3):e2014195118. https://doi.org/10.1073/pnas.2014195118.

54. Gao Y., Ma X., Lu H. et al. PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer. Oncol Rep. 2023;49(2):25. https://doi.org/10.3892/or.2022.8462.

55. Wang H., Gao P., Zheng J. Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells. Biochem Biophys Res Commun. 2014;451(4):556–61. https://doi.org/10.1016/j.bbrc.2014.08.014.

56. Hongo F., Garban H., Huerta-Yepez S. et al. Inhibition of the transcription factor Yin Yang 1 activity by S-nitrosation. Biochem Biophys Res Commun. 2005;336(2):692–701. https://doi.org/10.1016/j.bbrc.2005.08.150.

57. Yi C., Li G., Wang W. et al. Disruption of YY1-EZH2 interaction using synthetic peptides inhibits breast cancer development. Cancers (Basel). 2021;13(10):2402. https://doi.org/10.3390/cancers13102402.

58. Wu S., Zhang L., Deng J. et al. A novel micropeptide encoded by Y-Linked LINC00278 links cigarette smoking and AR signaling in male esophageal squamous cell carcinoma. Cancer Res. 2020;80(13):2790–803. https://doi.org/10.1158/0008-5472.CAN-19-3440.

59. Hosea R., Hillary S., Wu S., Kasim V. Targeting transcription Factor YY1 for cancer treatment: current strategies and future directions. Cancers (Basel). 2023;15(13):3506. https://doi.org/10.3390/cancers15133506.

60. Nie X., Chen H., Xiong Y. et al. Anisomycin has a potential toxicity of promoting cuproptosis in human ovarian cancer stem cells by attenuating YY1/lipoic acid pathway activation. J Cancer. 2022;13(14):3503–14. https://doi.org/10.7150/jca.77445.

61. Matsumura N., Huang Z., Baba T. et al. Yin Yang 1 modulates taxane response in epithelial ovarian cancer. Mol Cancer Res. 2009;7(2):210–20. https://doi.org/10.1158/1541-7786.MCR-08-0255.

62. Wu H., Xia L., Sun L. et al. RPL35A drives ovarian cancer progression by promoting the binding of YY1 to CTCF promoter. J Cell Mol Med. 2024;28(6):e18115. https://doi.org/10.1111/jcmm.18115.

63. Xia B., Li H., Yang S. et al. MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression. Tumour Biol. 2016;37(7):9157–67. https://doi.org/10.1007/s13277-016-4805-8.

64. Qian S., Wang W., Li M. Transcriptional factor Yin Yang 1 facilitates the stemness of ovarian cancer via suppressing miR-99a activity through enhancing its deacetylation level. Biomed Pharmacother. 2020;126:110085. https://doi.org/10.1016/j.biopha.2020.110085.

65. Tang Z., Xing F., Chen D. et al. In vivo toxicological evaluation of Anisomycin. Toxicol Lett. 2012;208(1):1–11. https://doi.org/10.1016/j.toxlet.2011.10.001.

66. Ye W., Ni Z., Yicheng S. et al. Anisomycin inhibits angiogenesis in ovarian cancer by attenuating the molecular sponge effect of the lncRNA-Meg3/miR-421/PDGFRA axis. Int J Oncol. 2019;55(6):1296–312. https://doi.org/10.3892/ijo.2019.4887.

67. Wu S., Hu Y.C., Liu H., Shi Y. Loss of YY1 impacts the heterochromatic state and meiotic double-strand breaks during mouse spermatogenesis. Mol Cell Biol. 2009;29(23):6245–56. https://doi.org/10.1128/MCB.00679-09.

68. Kim J.S., Chae J.H., Cheon Y.P., Kim C.G. Reciprocal localization of transcription factors YY1 and CP2c in spermatogonial stem cells and their putative roles during spermatogenesis. Acta Histochem. 2016;118(7):685–92. https://doi.org/10.1016/j.acthis.2016.08.005.

69. Chen L., Qiao L., Guo Y. et al. Localization and regulatory function of Yin Yang 1 (YY1) in chicken testis. Mol Genet Genomics. 2022;297(1):113–23. https://doi.org/10.1007/s00438-021-01840-8.

70. Deng Z., Wan M., Cao P. et al. Yin Yang 1 regulates the transcriptional activity of androgen receptor. Oncogene. 2009;28(42):3746–57. https://doi.org/10.1038/onc.2009.231.

71. Liu Q., Liang Z., Li L. et al. YY1 in prostate cancer: multidimensional oncogenicmechanisms and emerging therapeutic vulnerabilities. J Mol Histol. 2026;57(1):31. https://doi.org/10.1007/s10735-025-10683-1.

72. Huerta-Yepez S., Vega M., Garban H., Bonavida B. Involvement of the TNF-alpha autocrine-paracrine loop, via NF-kappaB and YY1, in the regulation of tumor cell resistance to Fas-induced apoptosis. Clin Immunol. 2006;120(3):297–309. https://doi.org/10.1016/j.clim.2006.03.015.

73. Kelleher Z.T., Matsumoto A., Stamler J.S., Marshall H.E. NOS2 regulation of NF-kappaB by S-nitrosylation of p65. J Biol Chem. 2007;282(42):30667–72. https://doi.org/10.1074/jbc.M705929200.