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ReviewOpen Accesscc iconby icon

The role of EZH2 in ocular diseases: a narrative review

    Yu Peng‡

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    ,
    Christine HT Bui‡

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    ,
    Xiu J Zhang

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    ,
    Jian S Chen

    Aier School of Ophthalmology, Central South University, Changsha, Hunan Province, 410000, China

    Aier Eye Institute, Changsha, Hunan Province, 410000, China

    Key Laboratory for Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou, Guangdong Province, 510000, China

    ,
    Clement C Tham

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    Hong Kong Eye Hospital, Kowloon, 999077, Hong Kong

    Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, 999077, Hong Kong

    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, 999077, Hong Kong

    ,
    Wai K Chu

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, 999077, Hong Kong

    ,
    Li J Chen

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, 999077, Hong Kong

    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, 999077, Hong Kong

    ,
    Chi P Pang

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, 999077, Hong Kong

    &
    Jason C Yam

    *Author for correspondence:

    E-mail Address: yamcheuksing@cuhk.edu.hk

    Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 999077, Hong Kong

    Hong Kong Eye Hospital, Kowloon, 999077, Hong Kong

    Department of Ophthalmology, Hong Kong Children’s Hospital, 999077, Hong Kong

    Department of Ophthalmology & Visual Sciences, Prince of Wales Hospital, 999077, Hong Kong

    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, 999077, Hong Kong

    Published Online:https://doi.org/10.2217/epi-2023-0147

    EZH2, acting as a catalytic subunit of PRC2 to catalyze lysine 27 in histone H3, induces the suppression of gene expression. EZH2 can regulate cell proliferation and differentiation of retinal progenitors, which are required for physiological retinal development. Meanwhile, an abnormal level of EZH2 has been observed in ocular tumors and other pathological tissues. This review summarizes the current knowledge on EZH2 in retinal development and ocular diseases, including inherited retinal diseases, ocular tumors, corneal injury, cataract, glaucoma, diabetic retinopathy and age-related retinal degeneration. We highlight the potential of targeting EZH2 as a precision therapeutic target in ocular diseases.

    Plain language summary

    EZH2 is a protein that helps to regulate the activity of genes in cells. It works as a part of a complex called PRC2 to control a chemical group called lysine 27 in histone H3 and then inhibit the expression of genes. EZH2 is important for the normal development of the retina. Abnormal levels of EZH2 are associated with various eye diseases. This review summarizes the role of EZH2 in different ocular diseases and the potential mechanisms. Targeting EZH2 may be a novel way to treat or prevent ocular diseases.

    Tweetable abstract

    Review discussing the role of EZH2 in retinal development and ocular diseases to highlight the potential of EZH2 as a precision therapeutic target for treating ocular diseases.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Varma R, Vajaranant TS, Burkemper B et al. Visual impairment and blindness in adults in the United States: demographic and geographic variations from 2015 to 2050. JAMA Ophthalmol. 134(7), 802–809 (2016).
    • 2. Wang L, Zhu Z, Scheetz J, He M. Visual impairment and ten-year mortality: the Liwan Eye Study. Eye 35(8), 2173–2179 (2021).
    • 3. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 23(7), 781–783 (2009).
    • 4. Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 174(3), 341–348 (2006).
    • 5. Vedschmidt SE, Stagner AM, Eagle RC Jr, Harocopos GJ, Dou Y, Rao RC. The targetable epigenetic tumor protein EZH2 is enriched in intraocular medulloepithelioma. Invest. Ophthalmol. Vis. Sci. 57(14), 6242–6246 (2016). • Demonstrates that EZH2 was highly expressed in moderately to poorly differentiated tumor cells.
    • 6. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647(1–2), 21–29 (2008).
    • 7. Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J. Hematol. Oncol. 13(1), 104 (2020).
    • 8. Zhang J, Taylor RJ, La Torre A et al. EZH2 maintains retinal progenitor proliferation, transcriptional integrity, and the timing of late differentiation. Dev. Biol. 403(2), 128–138 (2015). •• Suggests that EZH2 plays a critical role in retinal progenitor proliferation, as well as regulating the timing of late differentiation.
    • 9. Jin B, Zhang P, Zou H et al. Verification of EZH2 as a druggable target in metastatic uveal melanoma. Mol. Cancer 19(1), 52 (2020).
    • 10. Cao J, Pontes KC, Heijkants RC et al. Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target. J. Pathol. 245(4), 433–444 (2018).
    • 11. Khan M, Walters LL, Li Q et al. Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma. Lab. Invest. 95(11), 1278–1290 (2015). •• Shows that EZH2 might regulate human retinoblastoma tumorigenesis.
    • 12. Liao K, Cui Z, Zeng Y et al. Inhibition of enhancer of zeste homolog 2 prevents corneal myofibroblast transformation in vitro. Exp. Eye Res. 208, 108611 (2021).
    • 13. Zhang L, Wang L, Hu XB et al. MYPT1/PP1-mediated EZH2 dephosphorylation at S21 promotes epithelial-mesenchymal transition in fibrosis through control of multiple families of genes. Adv. Sci. (Weinh.) 9(14), e2105539 (2022).
    • 14. Thomas AA, Feng B, Chakrabarti S. ANRIL: a regulator of VEGF in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 58(1), 470–480 (2017).
    • 15. Di S, An X, Pang B et al. Yiqi Tongluo Fang could preventive and delayed development and formation of diabetic retinopathy through antioxidant and anti-inflammatory effects. Biomed. Pharmacother. 148, 112254 (2022).
    • 16. Mbefo M, Berger A, Schouwey K et al. Enhancer of zeste homolog 2 (EZH2) contributes to rod photoreceptor death process in several forms of retinal degeneration and its activity can serve as a biomarker for therapy efficacy. Int. J. Mol. Sci. 22(17), 9331 (2021). • Focuses on the role of EZH2 in the photoreceptor death process; demonstrates that EZH2 contributes to cell death and that the absence of the H3K27me3 mark may be a biomarker of the efficacy of EZH2 gene therapy.
    • 17. Wen X, Ding T, Li F et al. Interruption of aberrant chromatin looping is required for regenerating RB1 function and suppressing tumorigenesis. Commun. Biol. 5(1), 1036 (2022).
    • 18. Duraisamy AJ, Mishra M, Kowluru RA. Crosstalk between histone and DNA methylation in regulation of retinal matrix metalloproteinase-9 in diabetes. Invest. Ophthalmol. Vis. Sci. 58(14), 6440–6448 (2017).
    • 19. Zeng J, Zhang J, Sun Y et al. Targeting EZH2 for cancer therapy: from current progress to novel strategies. Eur. J. Med. Chem. 238, 114419 (2022).
    • 20. Völkel P, Dupret B, Le Bourhis X, Angrand PO. Diverse involvement of EZH2 in cancer epigenetics. Am. J. Transl. Res. 7(2), 175–193 (2015).
    • 21. Yamaguchi H, Hung MC. Regulation and role of EZH2 in cancer. Cancer Res. Treat. 46(3), 209–222 (2014).
    • 22. Viré E, Brenner C, Deplus R et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature 439(7078), 871–874 (2006).
    • 23. Kim E, Kim M, Woo DH et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23(6), 839–852 (2013).
    • 24. Fan T, Jiang S, Chung N et al. EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression. Mol. Cancer Res. 9(4), 418–429 (2011).
    • 25. Hernandez AJ, Zovoilis A, Cifuentes-Rojas C, Han L, Bujisic B, Lee JT. B2 and ALU retrotransposons are self-cleaving ribozymes whose activity is enhanced by EZH2. Proc. Natl Acad. Sci. USA 117(1), 415–425 (2020).
    • 26. Tabbal H, Septier A, Mathieu M et al. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness. Br. J. Cancer 121(5), 384–394 (2019).
    • 27. Rao RC, Tchedre KT, Malik MT et al. Dynamic patterns of histone lysine methylation in the developing retina. Invest. Ophthalmol. Vis. Sci. 51(12), 6784–6792 (2010).
    • 28. Rapicavoli NA, Poth EM, Zhu H, Blackshaw S. The long noncoding RNA Six3OS acts in trans to regulate retinal development by modulating Six3 activity. Neural Dev. 6, 32 (2011).
    • 29. Aldiri I, Moore KB, Hutcheson DA, Zhang J, Vetter ML. Polycomb repressive complex PRC2 regulates Xenopus retina development downstream of Wnt/β-catenin signaling. Development 140(14), 2867–2878 (2013).
    • 30. Iida A, Iwagawa T, Kuribayashi H et al. Histone demethylase JMJD3 is required for the development of subsets of retinal bipolar cells. Proc. Natl Acad. Sci. USA 111(10), 3751–3756 (2014).
    • 31. Iida A, Iwagawa T, Baba Y et al. Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation. Dev. Neurobiol. 75(9), 947–960 (2015). •• Fouses on the influence of EZH2 knockout in retinal proliferation and differentiation.
    • 32. Watanabe S, Murakami A. Regulation of retinal development via the epigenetic modification of histone H3. Adv. Exp. Med. Biol. 854, 635–641 (2016).
    • 33. Fujimura N, Kuzelova A, Ebert A et al. Polycomb repression complex 2 is required for the maintenance of retinal progenitor cells and balanced retinal differentiation. Dev. Biol. 433(1), 47–60 (2018).
    • 34. Andrews D, Oliviero G, De Chiara L et al. Unravelling the transcriptional responses of TGF-β: Smad3 and EZH2 constitute a regulatory switch that controls neuroretinal epithelial cell fate specification. FASEB J. 33(5), 6667–6681 (2019).
    • 35. Ben-Yosef T. Inherited retinal diseases. Int. J. Mol. Sci. 23(21), 13467 (2022).
    • 36. Zheng S, Xiao L, Liu Y et al. DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice. Cell Death Dis. 9(3), 310 (2018).
    • 37. Ueno K, Iwagawa T, Kuribayashi H et al. Transition of differential histone H3 methylation in photoreceptors and other retinal cells during retinal differentiation. Sci. Rep. 6, 29264 (2016).
    • 38. Yan N, Cheng L, Cho K et al. Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1. Sci. Rep. 6, 33887 (2016).
    • 39. Italiano A, Soria JC, Toulmonde M et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 19(5), 649–659 (2018).
    • 40. Morschhauser F, Tilly H, Chaidos A et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 21(11), 1433–1442 (2020).
    • 41. Gounder M, Schöffski P, Jones RL et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 21(11), 1423–1432 (2020).
    • 42. Song Y, Liu Y, Li ZM et al. SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial. Lancet Haematol. 9(7), e493–e503 (2022).
    • 43. Izutsu K, Ando K, Nishikori M et al. Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan. Cancer Sci. 112(9), 3627–3635 (2021).
    • 44. Vaswani RG, Gehling VS, Dakin LA et al. Identification of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J. Med. Chem. 59(21), 9928–9941 (2016).
    • 45. Yap TA, Winter JN, Giulino-Roth L et al. Phase I study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors. Clin. Cancer Res. 25(24), 7331–7339 (2019).
    • 46. Munakata W, Shirasugi Y, Tobinai K et al. Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma. Cancer Sci. 112(3), 1123–1131 (2021).
    • 47. Zauderer MG, Szlosarek PW, Le Moulec S et al. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet Oncol. 23(6), 758–767 (2022).
    • 48. Lu Q, Zhao N, Zha G, Wang H, Tong Q, Xin S. LncRNA HOXA11-AS exerts oncogenic functions by repressing p21 and miR-124 in uveal melanoma. DNA Cell Biol. 36(10), 837–844 (2017).
    • 49. Li Y, Zhang M, Feng H, Mahati S. The tumorigenic properties of EZH2 are mediated by miR-26a in uveal melanoma. Front. Mol. Biosci. 8, 713542 (2021).
    • 50. Zhang J, Liu G, Jin H et al. MicroRNA-137 targets EZH2 to exert suppressive functions in uveal melanoma via regulation of Wnt/β-catenin signaling and epithelial-to-mesenchymal transition. J. BUON 26(1), 173–181 (2021).
    • 51. Hou C, Xiao L, Ren X et al. EZH2-mediated H3K27me3 is a predictive biomarker and therapeutic target in uveal melanoma. Front. Genet. 13, 1013475 (2022).
    • 52. Zhao Y, Cheng Y, Qu Y. The role of EZH2 as a potential therapeutic target in retinoblastoma. Exp. Eye Res. 227, 109389 (2023). • Shows that a high level of EZH2 in retinoblastoma tissues was significantly associated with poor overall survival. Inhibition of EZH2 is a potential target for anti-retinoblastoma treatment.
    • 53. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology 118(9), 1881–1885 (2011).
    • 54. Smit KN, Jager MJ, De Klein A, Kiliç E. Uveal melanoma: towards a molecular understanding. Prog. Retin. Eye Res. 75, 100800 (2020).
    • 55. Cheng Y, Li Y, Huang X, Wei W, Qu Y. Expression of EZH2 in uveal melanomas patients and associations with prognosis. Oncotarget 8(44), 76423–76431 (2017).
    • 56. Wu X, Yuan Y, Ma R, Xu B, Zhang R. lncRNA SNHG7 affects malignant tumor behaviors through downregulation of EZH2 in uveal melanoma cell lines. Oncol. Lett. 19(2), 1505–1515 (2020).
    • 57. Chen X, He D, Dong XD et al. MicroRNA-124a is epigenetically regulated and acts as a tumor suppressor by controlling multiple targets in uveal melanoma. Invest. Ophthalmol. Vis. Sci. 54(3), 2248–2256 (2013).
    • 58. Rossi E, Schinzari G, Maiorano BA et al. Conjunctival melanoma: genetic and epigenetic insights of a distinct type of melanoma. Int J Mol Sci 20(21), 5447 (2019).
    • 59. Mudhar HS, Salvi SS, Pissaloux D, De La Fouchardiere A. Single time frame overview of the genetic changes in conjunctival melanoma from intraepithelial disease to invasive melanoma: a study of 4 exenteration specimens illustrating the potential role of cyclin D1. Ocul. Oncol. Pathol. 8(1), 52–63 (2022).
    • 60. Kaewkhaw R, Rojanaporn D. Retinoblastoma: etiology, modeling, and treatment. Cancers (Basel) 12(8), 2304 (2020).
    • 61. Fabian ID, Onadim Z, Karaa E et al. The management of retinoblastoma. Oncogene 37(12), 1551–1560 (2018).
    • 62. Dimaras H, Corson TW, Cobrinik D et al. Retinoblastoma. Nat. Rev. Dis. Primers 1, 15021 (2015).
    • 63. Ishak CA, Marshall AE, Passos DT et al. An RB–EZH2 complex mediates silencing of repetitive DNA sequences. Mol. Cell 64(6), 1074–1087 (2016).
    • 64. Lei Q, Shen F, Wu J, Zhang W, Wang J, Zhang L. MiR-101, downregulated in retinoblastoma, functions as a tumor suppressor in human retinoblastoma cells by targeting EZH2. Oncol. Rep. 32(1), 261–269 (2014).
    • 65. Saunders T, Margo CE. Intraocular medulloepithelioma. Arch. Pathol. Lab. Med. 136(2), 212–216 (2012).
    • 66. Edward DP, Alkatan H, Rafiq Q et al. MicroRNA profiling in intraocular medulloepitheliomas. PLOS ONE 10(3), e0121706 (2015).
    • 67. Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog. Retin. Eye Res. 18(4), 529–551 (1999).
    • 68. Wilson SE. Corneal wound healing. Exp. Eye Res. 197, 108089 (2020).
    • 69. Ljubimov AV, Saghizadeh M. Progress in corneal wound healing. Prog. Retin. Eye Res. 49, 17–45 (2015).
    • 70. Kamil S, Mohan RR. Corneal stromal wound healing: major regulators and therapeutic targets. Ocul. Surf. 19, 290–306 (2021).
    • 71. Zhao X, Song W, Chen Y, Liu S, Ren L. Collagen-based materials combined with microRNA for repairing cornea wounds and inhibiting scar formation. Biomater. Sci. 7(1), 51–62 (2018).
    • 72. Shu DY, Lovicu FJ. Myofibroblast transdifferentiation: the dark force in ocular wound healing and fibrosis. Prog. Retin. Eye Res. 60, 44–65 (2017).
    • 73. Myrna KE, Pot SA, Murphy CJ. Meet the corneal myofibroblast: the role of myofibroblast transformation in corneal wound healing and pathology. Vet. Ophthalmol. 12(Suppl. 1), 25–27 (2009).
    • 74. Wilson SE. Corneal myofibroblasts and fibrosis. Exp. Eye Res. 201, 108272 (2020).
    • 75. Wan S-S, Pan Y-M, Yang W-J, Rao Z-Q, Yang Y-N. Inhibition of EZH2 alleviates angiogenesis in a model of corneal neovascularization by blocking FoxO3a-mediated oxidative stress. FASEB J. 34(8), 10168–10181 (2020).
    • 76. Thompson J, Lakhani N. Cataracts. Prim. Care 42(3), 409–423 (2015).
    • 77. Liu YC, Wilkins M, Kim T, Malyugin B, Mehta JS. Cataracts. Lancet 390(10094), 600–612 (2017).
    • 78. Gao M, Huang Y, Wang L et al. HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators. Cell Death Dis. 8(10), e3082 (2017).
    • 79. Mou L, Xu JY, Li W et al. Identification of vimentin as a novel target of HSF4 in lens development and cataract by proteomic analysis. Invest. Ophthalmol. Vis. Sci. 51(1), 396–404 (2010).
    • 80. Cui X, Du C, Wan S et al. Deficiency of heat shock factor 4 promotes lens epithelial cell senescence through upregulating p21cip1 expression. Biochim. Biophys. Acta Mol. Basis Dis. 1867(11), 166233 (2021).
    • 81. Lee CM, Afshari NA. The global state of cataract blindness. Curr. Opin. Ophthalmol. 28(1), 98–103 (2017).
    • 82. Wormstone IM, Wang L, Liu CS. Posterior capsule opacification. Exp. Eye Res. 88(2), 257–269 (2009).
    • 83. Wormstone IM, Eldred JA. Experimental models for posterior capsule opacification research. Exp. Eye Res. 142, 2–12 (2016).
    • 84. Wormstone IM, Wormstone YM, Smith AJO, Eldred JA. Posterior capsule opacification: what's in the bag? Prog. Retin. Eye Res. 82, 100905 (2021).
    • 85. Dong N, Xu B, Xu J. EGF-Mediated overexpression of Myc attenuates miR-26b by recruiting HDAC3 to induce epithelial–mesenchymal transition of lens epithelial cells. Biomed. Res. Int. 2018, 7148023 (2018).
    • 86. Imaizumi T, Kurosaka D, Tanaka U, Sakai D, Fukuda K, Sanbe A. Topical administration of a ROCK inhibitor prevents anterior subcapsular cataract induced by UV-B irradiation. Exp. Eye Res. 181, 145–149 (2019).
    • 87. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog. Retin. Eye Res. 31(2), 152–181 (2012).
    • 88. Fry LE, Fahy E, Chrysostomou V et al. The coma in glaucoma: retinal ganglion cell dysfunction and recovery. Prog. Retin. Eye Res. 65, 77–92 (2018).
    • 89. Xiao L, Hou C, Cheng L, Zheng S, Zhao L, Yan N. DZNep protects against retinal ganglion cell death in an NMDA-induced mouse model of retinal degeneration. Exp. Eye Res. 212, 108785 (2021).
    • 90. Cheng L, Wong LJ, Yan N et al. Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury. PLOS ONE 13(2), e0191853 (2018).
    • 91. Zhou RR, Li HB, You QS et al. Silencing of GAS5 alleviates glaucoma in rat models by reducing retinal ganglion cell apoptosis. Hum. Gene Ther. 30(12), 1505–1519 (2019).
    • 92. Zhang N, Cao W, He X, Xing Y, Yang N. Long non-coding RNAs in retinal ganglion cell apoptosis. Cell. Mol. Neurobiol. 43(2), 561–574 (2023).
    • 93. Kowluru RA, Mohammad G, Dos Santos JM, Zhong Q. Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage. Diabetes 60(11), 3023–3033 (2011).
    • 94. Huang Y, Yu SH, Zhen WX et al. Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2. Theranostics 11(14), 6891–6904 (2021).
    • 95. Delgado-Olguín P, Dang LT, He D et al. Ezh2-mediated repression of a transcriptional pathway upstream of Mmp9 maintains integrity of the developing vasculature. Development 141(23), 4610–4617 (2014).
    • 96. Song Z, Wu W, Chen M et al. Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2. J. Virol. 92(24), e00909–18 (2018).
    • 97. Yang LH, Du P, Liu W et al. LncRNA ANRIL promotes multiple myeloma progression and bortezomib resistance by EZH2-mediated epigenetically silencing of PTEN. Neoplasma 68(4), 788–797 (2021).
    • 98. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog. Retin. Eye Res. 22(1), 1–29 (2003).
    • 99. Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye 28(5), 510–520 (2014).
    • 100. Yang Y, Liu Y, Li Y et al. MicroRNA-15b targets VEGF and inhibits angiogenesis in proliferative diabetic retinopathy. J. Clin. Endocrinol. Metab. 105(11), 3404–3415 (2020).
    • 101. Wong TY, Cheung CM, Larsen M, Sharma S, Simó R. Diabetic retinopathy. Nat. Rev. Dis. Primers 2, 16012 (2016).
    • 102. Ruiz MA, Feng B, Chakrabarti S. Polycomb repressive complex 2 regulates miR-200b in retinal endothelial cells: potential relevance in diabetic retinopathy. PLOS ONE 10(4), e0123987 (2015).
    • 103. Biswas S, Thomas AA, Feng B et al. MALAT1 and HOTAIR – key epigenetic regulators in diabetic retinopathy. Diabetes 67(Suppl. 1), 240-OR (2018).
    • 104. Di S, An X, Pang B et al. Yiqi Tongluo Fang could preventive and delayed development and formation of diabetic retinopathy through antioxidant and anti-inflammatory effects. Biomed. Pharmacother. 148, 112254 (2022).
    • 105. Olivares AM, Jelcick AS, Reinecke J et al. Multimodal regulation orchestrates normal and complex disease states in the retina. Sci. Rep. 7(1), 690 (2017).
    • 106. Peng Y, Liao K, Tan F et al. Suppression of EZH2 inhibits TGF-β1-induced EMT in human retinal pigment epithelial cells. Exp. Eye Res. 222, 109158 (2022).
    • 107. Lee HE, Ayarpadikannan S, Kim HS. Role of transposable elements in genomic rearrangement, evolution, gene regulation and epigenetics in primates. Genes Genet. Syst. 90(5), 245–257 (2015).
    • 108. Kaneko H, Dridi S, Tarallo V et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471(7338), 325–330 (2011).
    • 109. Tarallo V, Hirano Y, Gelfand BD et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149(4), 847–859 (2012).
    • 110. Gelfand BD, Wright CB, Kim Y et al. Iron toxicity in the retina requires Alu RNA and the NLRP3 inflammasome. Cell Rep. 11(11), 1686–1693 (2015).
    • 111. Zhu S, Liu M, Zhu F, Yu X, Wen J, Li C. Targeting EZH2 prevents the occurrence and mitigates the development of Sjögren’s syndrome in mice. Int. Immunopharmacol. 110, 109073 (2022).
    • 112. He C, Yang Y, Chen Z et al. EZH2 promotes T follicular helper cell differentiation through enhancing STAT3 phosphorylation in patients with primary Sjögren’s syndrome. Front. Immunol. 13, 922871 (2022).
    • 113. Katoh M. Mutation spectra of histone methyltransferases with canonical SET domains and EZH2-targeted therapy. Epigenomics 8(2), 285–305 (2016).