Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5247_Библиотеки_им_академика_М_И_Перельмана.pdf
6 Prostate Cancer andWNT/STAT3 Signaling
147
essential for the synthesis of immunosuppressive factors and for suppressing the
expression of critical immune activation regulators.
6.8 Conclusion
In conclusion, prostate cancer treatment may benet from focusing on the STAT3
and Wnt signaling pathways. In order to create efcient treatment plans and biomarkers to inform therapy choices and enhance patient care, further study is required
to understand how these pathways interact.
References
1. Rawla P.Epidemiology of prostate cancer. World J Oncol. 2019;10(2):63–89.
2. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, etal. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7(1):3.
3. Zhang Y, Wang X.Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol.
2020;13(1):165.
4. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, et al.
Signal transducer and activator of transcription-3, inammation, and cancer: how intimate is
the relationship? Ann N Y Acad Sci. 2009;1171:59–76.
5. Yu H, Pardoll D, Jove R.STATs in cancer inammation and immunity: a leading role for
STAT3. Nat Rev Cancer. 2009;9(11):798–809.
6. Fragoso MA, Patel AK, Nakamura RE, Yi H, Surapaneni K, Hackam AS.The Wnt/β-catenin
pathway cross-talks with STAT3 signaling to regulate survival of retinal pigment epithelium
cells. PLoS One. 2012;7(10):e46892.
7. Wang C, Chen Q, Xu H.Wnt/β-catenin signal transduction pathway in prostate cancer and
associated drug resistance. Discov Oncol. 2021;12(1):40.
8. Yang PL, Liu LX, Li EM, Xu LY.STAT3, the challenge for chemotherapeutic and radiotherapeutic efcacy. Cancers (Basel). 2020;12(9):2459.
9. Cadigan KM, Nusse R.Wnt signaling: a common theme in animal development. Genes Dev.
1997;11(24):3286–305.
10. Pster AS, Kühl M.Of Wnts and ribosomes. Prog Mol Biol Transl Sci. 2018;153:131–55.
11. MacDonald BT, He X. Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold
Spring Harb Perspect Biol. 2012;4(12):a007880.
12. Nusse R, Clevers H.Wnt/β-catenin signaling, disease, and emerging therapeutic modalities.
Cell. 2017;169(6):985–99.
13. Shang S, Hua F, Hu ZW.The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017;8(20):33972–89.
14. García de Herreros A, Duñach M.Intracellular signals activated by canonical Wnt ligands
independent of GSK3 inhibition and β-catenin stabilization. Cells. 2019;8(10):1148.
15. Arend RC, Londoño-Joshi AI, Straughn JM Jr, Buchsbaum DJ.The Wnt/β-catenin pathway in
ovarian cancer: a review. Gynecol Oncol. 2013;131(3):772–9.
16. Tian J, He H, Lei G. Wnt/β-catenin pathway in bone cancers. Tumour Biol.
2014;35(10):9439–45.
17. Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature
review. World J Exp Med. 2015;5(2):84–102.
148
18. Liu C, Takada K, Zhu D.Targeting Wnt/β-catenin pathway for drug therapy. Med Drug Discov.
2020;8:100066.
19. Yu X, Wang Y, DeGraff DJ, Wills ML, Matusik RJ.Wnt/β-catenin activation promotes prostate
tumor progression in a mouse model. Oncogene. 2011;30(16):1868–79.
20. Moparthi L, Pizzolato G, Koch S.Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer. Proc Natl Acad Sci USA. 2019;116(44):22189–95.
21. Voeller HJ, Truica CI, Gelmann EP.Beta-catenin mutations in human prostate cancer. Cancer
Res. 1998;58(12):2520–3.
22. Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D, etal. Up-regulation of Wnt-1
and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential
pathogenetic and prognostic implications. Cancer. 2004;101(6):1345–56.
23. de la Taille A, Rubin MA, Chen MW, Vacherot F, de Medina SG, Burchardt M, etal. Betacatenin- related anomalies in apoptosis-resistant and hormone-refractory prostate cancer cells.
Clin Cancer Res. 2003;9(5):1801–7.
24. Thiele S, Rauner M, Goettsch C, Rachner TD, Benad P, Fuessel S, et al. Expression prole of WNT molecules in prostate cancer and its regulation by aminobisphosphonates. J Cell
Biochem. 2011;112(6):1593–600.
25. Katoh M.Frequent up-regulation of WNT2in primary gastric cancer and colorectal cancer. Int
J Oncol. 2001;19(5):1003–7.
26. Hall CL, Baco A, Dai J, Aaronson SA, Keller ET.Prostate cancer cells promote osteoblastic
bone metastases through Wnts. Cancer Res. 2005;65(17):7554–60.
27. Verras M, Brown J, Li X, Nusse R, Sun Z.Wnt3a growth factor induces androgen receptormediated transcription and enhances cell growth in human prostate cancer cells. Cancer Res.
2004;64(24):8860–6.
28. Yokoyama NN, Shao S, Hoang BH, Mercola D, Zi X.Wnt signaling in castration-resistant
prostate cancer: implications for therapy. Am J Clin Exp Urol. 2014;2(1):27–44.
29. Zhao S, Ye X, Xiao L, Lian X, Feng Y, Li F, etal. MiR-26a inhibits prostate cancer progression
by repression of Wnt5a. Tumour Biol. 2014;35(10):9725–33.
30. Sandsmark E, Hansen AF, Selnæs KM, Bertilsson H, Bon AM, Wright AJ, etal. A novel noncanonical Wnt signature for prostate cancer aggressiveness. Oncotarget. 2017;8(6):9572–86.
31. Zhu H, Mazor M, Kawano Y, Walker MM, Leung HY, Armstrong K, etal. Analysis of Wnt
gene expression in prostate cancer: mutual inhibition by WNT11 and the androgen receptor.
Cancer Res. 2004;64(21):7918–26.
32. Madueke I, Hu WY, Hu D, Swanson SM, Vander Griend D, Abern M, etal. The role of WNT10B
in normal prostate gland development and prostate cancer. Prostate. 2019;79(14):1692–704.
33. Schneider JA, Logan SK.Revisiting the role of Wnt/β-catenin signaling in prostate cancer.
Mol Cell Endocrinol. 2018;462(Pt A):3–8.
34. Nikolskii AA, Shilovskiy IP, Barvinskaia ED, Korneev AV, Sundukova MS, Khaitov MR.Role
of STAT3 transcription factor in pathogenesis of bronchial asthma. Biochemistry (Mosc).
2021;86(11):1489–501.
35. Hillmer EJ, Zhang H, Li HS, Watowich SS.STAT3 signaling in immunity. Cytokine Growth
Factor Rev. 2016;31:1–15.
36. Chen Q, Lv J, Yang W, Xu B, Wang Z, Yu Z, etal. Targeted inhibition of STAT3 as a potential
treatment strategy for atherosclerosis. Theranostics. 2019;9(22):6424–42.
37. Garg M, Shanmugam MK, Bhardwaj V, Goel A, Gupta R, Sharma A, et al. The pleiotropic
role of transcription factor STAT3in oncogenesis and its targeting through natural products for
cancer prevention and therapy. Med Res Rev. 2020;
38. Szelag M, Piaszyk-Borychowska A, Plens-Galaska M, Wesoly J, Bluyssen HA. Targeted
inhibition of STATs and IRFs as a potential treatment strategy in cardiovascular disease.
Oncotarget. 2016;7(30):48788–812.
39. Yang R, Song Y, Shakoor K, Yi W, Peng C, Liu S.Insights into the role of STAT3in intrahepatic cholangiocarcinoma (Review). Mol Med Rep. 2022;25(5):171.
S. Etemad et al.
6 Prostate Cancer andWNT/STAT3 Signaling
40. Chalikonda G, Lee H, Sheik A, Huh YS.Targeting key transcriptional factor STAT3in colorectal cancer. Mol Cell Biochem. 2021;476(9):3219–28.
41. Ashrazadeh M, Gholami MH, Mirzaei S, Zabolian A, Haddadi A, Farahani MV, etal. Dual
relationship between long non-coding RNAs and STAT3 signaling in different cancers: new
insight to proliferation and metastasis. Life Sci. 2021;270:119006.
42. Hussain Y, Mirzaei S, Ashrazadeh M, Zarrabi A, Hushmandi K, Khan H, etal. Quercetin and
its nano-scale delivery systems in prostate cancer therapy: paving the way for cancer elimination and reversing chemoresistance. Cancers (Basel). 2021;13(7):1602.
43. Geethadevi A, Nair A, Parashar D, Ku Z, Xiong W, Deng H, etal. Oncostatin M receptortargeted antibodies suppress STAT3 signaling and inhibit ovarian cancer growth. Cancer Res.
2021;81(20):5336–52.
44. Xiong W, Chen Y, Zhang C, Li J, Huang H, Zhu Y, et al. Pharmacologic inhibition of
IL11/STAT3 signaling increases MHC-I expression and T cell inltration. J Transl Med.
2023;21(1):416.
45. Zhi L, Zhao L, Zhang X, Liu W, Gao B, Wang F, etal. SLCO1B3 promotes colorectal cancer
tumorigenesis and metastasis through STAT3. Aging (Albany NY). 2021;13(18):22164–75.
46. Li M, Chen X, Wang X, Wei X, Wang D, Liu X, etal. RSL3 enhances the antitumor effect
of cisplatin on prostate cancer cells via causing glycolysis dysfunction. Biochem Pharmacol.
2021;192:114741.
47. Huang X, Fang J, Lai W, Hu Y, Li L, Zhong Y, etal. IL-6/STAT3 axis activates Glut5 to regulate fructose metabolism and tumorigenesis. Int J Biol Sci. 2022;18(9):3668–75.
48. Sadrkhanloo M, Paskeh MDA, Hashemi M, Raesi R, Motahhary M, Saghari S, etal. STAT3
signaling in prostate cancer progression and therapy resistance: an oncogenic pathway with
diverse functions. Biomed Pharmacother. 2023;158:114168.
49. Jung YY, Ko JH, Um JY, Chinnathambi A, Alharbi SA, Sethi G, etal. LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway. J Cell Physiol. 2021;236(7):5253–64.
50. Philp LK, Rockstroh A, Sadowski MC, Taherian Fard A, Lehman M, Tevz G, et al. Leptin
antagonism inhibits prostate cancer xenograft growth and progression. Endocr Relat Cancer.
2021;28(5):353–75.
51. Burton AJ, Gilbert R, Tilling K, Langdon R, Donovan JL, Holly JMP, etal. Circulating adiponectin and leptin and risk of overall and aggressive prostate cancer: a systematic review and
meta-analysis. Sci Rep. 2021;11(1):320.
52. Gorrab A, Pagano A, Ayed K, Chebil M, Derouiche A, Kovacic H, etal. Leptin promotes
prostate cancer proliferation and migration by stimulating STAT3 pathway. Nutr Cancer.
2021;73(7):1217–27.
53. Chen X, Zhou J, Li X, Wang X, Lin Y, Wang X.Exosomes derived from hypoxic epithelial
ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype. Cancer Lett. 2018;435:80–91.
54. Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti-tumour strategies aiming to target tumourassociated macrophages. Immunology. 2013;138(2):93–104.
55. Binnemars-Postma K, Storm G, Prakash J.Nanomedicine strategies to target tumor-associated
macrophages. Int J Mol Sci. 2017;18(5):979.
56. Anfray C, Ummarino A, Andón FT, Allavena P.Current strategies to target tumor-associatedmacrophages to improve anti-tumor immune responses. Cells. 2019;9(1):46.
57. Tian X, Wu Y, Yang Y, Wang J, Niu M, Gao S, etal. Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating
Wnt/β-catenin signaling. Mol Oncol. 2020;14(2):462–83.
58. Jiang H, Deng W, Zhu K, Zeng Z, Hu B, Zhou Z, etal. LINC00467 promotes prostate cancer
progression via M2 macrophage polarization and the miR-494-3p/STAT3 Axis. Front Oncol.
2021;11:661431.
149
150
59. Tan B, Chen X, Fan Y, Yang Y, Yang J, Tan L.STAT3 phosphorylation is required for the
HepaCAM-mediated inhibition of castration-resistant prostate cancer cell viability and metastasis. Prostate. 2021;81(9):603–11.
60. Guo Y, Zang Y, Lv L, Cai F, Qian T, Zhang G, etal. IL-8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NF-κB pathway in prostate cancer. Mol Med Rep.
2017;16(6):9035–42.
61. Mirzaei S, Paskeh MDA, Okina E, Gholami MH, Hushmandi K, Hashemi M, etal. Molecular
landscape of LncRNAs in prostate cancer: a focus on pathways and therapeutic targets for
intervention. J Exp Clin Cancer Res. 2022;41(1):214.
62. Xing Z, Li S, Liu Z, Zhang C, Meng M, Bai Z.The long non-coding RNA LINC00473 contributes to cell proliferation via JAK-STAT3 signaling pathway by regulating miR-195-5p/SEPT2
axis in prostate cancer. Biosci Rep. 2020;40(9):BSR20191850.
63. Liu C, Lin P, Zhao J, Xie H, Li R, Yang X, et al. Knockdown of long noncoding RNA
AC245100.4 inhibits the tumorigenesis of prostate cancer cells via the STAT3/NR4A3 axis.
Epigenomics. 2021;13(20):1591–605.
64. Wei X, Hou Y, Zhang Y, Zhang H, Sun Z, Meng X, etal. Long non-coding RNA MAGI2-AS3
inactivates STAT3 pathway to inhibit prostate cancer cell proliferation via acting as a
microRNA-424-5p sponge. J Cancer. 2022;13(1):343–53.
65. Ma J-B, Bai J-Y, Zhang H-B, Jia J, Shi Q, Yang C, etal. KLF5 inhibits STAT3 activity and
tumor metastasis in prostate cancer by suppressing IGF1 transcription cooperatively with
HDAC1. Cell Death Dis. 2020;11(6):466.
66. Sikka S, Shanmugam MK, Siveen KS, Ong TH, Yang MH, Lee JH, etal. Diosgenin attenuates
tumor growth and metastasis in transgenic prostate cancer mouse model by negatively regulating both NF-κB/STAT3 signaling cascades. Eur J Pharmacol. 2021;906:174274.
67. Cho KH, Choi MJ, Jeong KJ, Kim JJ, Hwang MH, Shin SC, etal. A ROS/STAT3/HIF-1α signaling cascade mediates EGF-induced TWIST1 expression and prostate cancer cell invasion.
Prostate. 2014;74(5):528–36.
68. Grant WB.Vitamin D may reduce prostate cancer metastasis by several mechanisms including
blocking Stat3. Am J Pathol. 2008;173(5):1589–90.
69. Tong D, Liu Q, Liu G, Xu J, Lan W, Jiang Y, etal. Metformin inhibits castration-induced EMT
in prostate cancer by repressing COX2/PGE2/STAT3 axis. Cancer Lett. 2017;389:23–32.
70. Babaei G, Khadem Ansari MH, Aziz SG, Bazl MR.Alantolactone inhibits stem-like cell phenotype, chemoresistance and metastasis in PC3 cells through STAT3 signaling pathway. Res
Pharm Sci. 2020;15(6):551–62.
71. Vanharanta S, Massagué J.Origins of metastatic traits. Cancer Cell. 2013;24(4):410–21.
72. Jacob LS, Vanharanta S, Obenauf AC, Pirun M, Viale A, Socci ND, etal. Metastatic competence can emerge with selection of preexisting oncogenic alleles without a need of new mutations. Cancer Res. 2015;75(18):3713–9.
73. Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr HA, Delaloye JF, et al.
Interactions between cancer stem cells and their niche govern metastatic colonization. Nature.
2011;481(7379):85–9.
74. Kim SJ, Garcia-Recio S, Creighton CJ, Perou CM, Rosen JM. Alterations in Wnt- and/or
STAT3 signaling pathways and the immune microenvironment during metastatic progression.
Oncogene. 2019;38(31):5942–58.
75. Koushyar S, Meniel VS, Phesse TJ, Pearson HB.Exploring the Wnt pathway as a therapeutic
target for prostate cancer. Biomol Ther. 2022;12(2):309.
76. Kim SJ, Kang HG, Kim K, Kim H, Zetterberg F, Park YS, etal. Crosstalk between WNT and
STAT3 is mediated by galectin-3in tumor progression. Gastric Cancer. 2021;24(5):1050–62.
77. Han Z, Wang X, Ma L, Chen L, Xiao M, Huang L, etal. Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer. Oncotarget.
2014;5(18):8416–28.
78. Bishop JL, Thaper D, Zoubeidi A.The multifaceted roles of STAT3 signaling in the progression of prostate cancer. Cancers (Basel). 2014;6(2):829–59.
S. Etemad et al.
6 Prostate Cancer andWNT/STAT3 Signaling
79. Murillo-Garzón V, Kypta R. WNT signalling in prostate cancer. Nat Rev Urol.
2017;14(11):683–96.
80. Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X.Targeting STAT3in cancer immunotherapy.
Mol Cancer. 2020;19(1):145.
151
Chapter 7
Prostate Cancer andEZH2 Signaling
MohammedKavei, SiavashSeifollahyFakhr, AfsanehMousaei, BitaGhaffari,
NazaninFatemehFadavinia, TaraNorooziYeganeh, NasimEbrahimi,
MostafaHaji-Fatahaliha, andAmirRezaAref
Abstract Enhancer of zeste homolog 2 (EZH2), a member of the Polycomb group
(PcG) proteins, functions as a fundamental component of the polycomb repressive
complex 2 (PRC2), with two other core subunits. The enzyme has histone methyl-
M. Kavei
Department of Biology, Faculty of Science, Arak University, Arak, Iran
S. S. Fakhr
Department of Biotechnology, Faculty of Applied Ecology, Agricultural Science and
Biotechnology, Campus Hamar, Inland Norway University of Applied Sciences,
Hamar, Norway
A. Mousaei
Department of Biology, College of Science, Qaemshahr Branch, Islamic Azad University,
Qaem Shahr, Mazandaran, Iran
B. Ghaffari
Department of Cell and Molecular Biology, Faculty of Science, Kharazmi University,
Karaj, Iran
N. F. Fadavinia
Department of Basic Sciences, Garmsar Branch, Islamic Azad University, Garmsar, Iran
T. N. Yeganeh
Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University,
Tehran, Iran
N. Ebrahimi (*)
Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of
Science and Technology, University of Isfahan, Isfahan, Iran
M. Haji-Fatahaliha
Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences,
Tabriz, Iran
A. R. Aref (*)
Mass General Cancer Center, Department of Surgery, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA
Broad Institute of MIT and Harvard, Harvard Medical School, Cambridge, MA, USA
e-mail: aaref@mgh.harvard.edu
Ltd. 2024
G. Sethi et al. (eds.), Prostate Cancer: Molecular Events and Therapeutic
Modalities, https://doi.org/10.1007/978-981-97-4612-5_7
153© The Author(s), under exclusive license to Springer Nature Singapore Pte
154
M. Kavei et al.
transferase (MTase) activity, which selectively facilitates the methylation of histone
3 lysine 27 (H3K27) on promoters of target genes. PRC2 functions as epigenetic
silencers that have considerable importance in maintaining cellular identity and preserving the pluripotency of embryonic stem cells. Over the course of the last
20years, a growing body of data has provided support for the presence of mutations
in the EZH2 gene and/or its upregulation in several hematological malignancies and
solid tumors, particularly prostate cancer. Moreover, EZH2 is known as one of the
most increased genes in neuroendocrine prostate tumors, which exhibit increased
abundance as a result of the therapeutic administration of high-afnity inhibitors
targeting the androgen receptor system. Numerous studies have shown the epigenetic roles of EZH2in the silencing of tumor suppressor factors and the facilitation
of carcinogenesis. However, there have been reports of inconsistencies between
EZH2 and H3K27 methylation. Moreover, the effectiveness of enzyme inhibitors
targeting EZH2in prostate cancer has been demonstrated to have constraints, highlighting the need for a more thorough understanding of the many activities of EZH2.
In this chapter, we will begin by examining the regulatory mechanisms that govern
the classical activities of EZH2 as a histone methyltransferase (MTase). Additionally,
we will provide an overview of the multiple mechanisms engaged in bringing the
PRC2 to the chromatin. Furthermore, in this chapter, we provide a comprehensive
overview of other substrates of EZH2 that are not histones. Additionally, we examine the impact of post-translational changes on EZH2, which may inuence its substrate selectivity. In conclusion, we provide a summary of the additional roles of
EZH2 that go beyond its role as an MTase and/or a component of the PRC2.
Specically, we highlight its involvement as a transcriptional cofactor and explore
the potential for therapeutic targeting of EZH2in the context of prostate cancer.
Keywords Androgen receptor · Neuroendocrine prostate cancer · Posttranslational modications · Polycomb repressive complex · Epigenetic regulation
7.1 Introduction
Transcription and its regulation represent pivotal processes determining cellular
fate, and it is evident that disruptions in the factors involved in transcription participate in the progression of cancer. Genetic or epigenetic alterations in transcription
result in the onset and advancement of cancer. Enhancer of zeste homolog 2 (EZH2),
a crucial member of the Polycomb group (PcG) gene family due to its determinative
role in transcriptional repression, holds particular signicance in cancer-related
studies. The polycomb repressive complex 2 (PRC2) is a nuclear protein complex
of PcG that silences transcription and gene expression through chromatin structure
modulation [1]. Within this complex, EZH2 acts as the catalytic subunit, resulting
in trimethylation of Lys-27 on histone 3 (H3K27me3) [1, 2]. This epigenetic altera-
tion modies chromatin structure, leading to suppression of gene transcription. In
7 Prostate Cancer andEZH2 Signaling
general, the process of H3K27me3 represents a highly critical and determinant epigenetic event in the fate of stem cells and tissue development [3].
One of the additional roles of PRC2 includes the methylation of non-histone
proteins such as the transcription factor GATA binding protein 4 (GATA4) [4]. It is
noteworthy that EZH2 can also independently interact with other proteins and participate in the activation of downstream genes or methylation of non-histone targets
apart from PRC2 [5–7]. As mentioned earlier, EZH2 orchestrates the regulation of
autophagy, apoptosis [8], and cell cycle progression [9]. Additionally, it is involved
in DNA repair, cell senescence inhibition [10], cellular lineage determination, and
signaling pathway modulation [11]. Thus, the diverse roles of EZH2in various cellular processes are associated with many cancers, including prostate cancer [12].
Given the signicant role of EZH2in cancer, it has garnered attention as a target
for targeted therapies and novel treatment strategies. This chapter delves into the
role of EZH2in the initiation and progression of prostate cancer, metastasis, drug
resistance, and immune regulation, in addition to its potential as a therapeutic target
in emerging approaches, such as EZH2 methyltransferase (MTase) activity inhibitors, EZH2 degradation inducers, and combination therapies with other treatment
modalities.
155
7.2 An Overview ofEZH2
7.2.1 The Structure ofEZH2
The EZH2 gene consists of 20 exons, ultimately encoding a 746 amino acid protein,
located at position 7q35 [13]. The EZH2 protein is composed of ve domains,
namely Domain I, II, EED-interaction domain (EID), C-terminal suppressor of variegation 39, enhancer of zeste and trithorax domain ([su(var)3-9, enhancer-of-zeste
and trithorax]SET domain), and cysteine-rich domain (CXC domain) [2, 14]. The
SET domain is predominantly essential for the histone methyltransferase activity of
EZH2. The N-terminal domains serve as the primary sites for protein-protein interactions, contributing to the assembly of partner subunits and the proper function of
PRC2 [2].
7.2.2 EZH2 Action Modes
With the help of its SET domain, EZH2 primarily functions as a histone methyltransferase, and in either a PRC2-dependent or independent manner, it may coactivate or inhibit transcription.
Contrary to the previous notion of histones solely acting as packaging proteins in
the nucleosome core, histones establish dynamic interactions between DNA and
other cellular components. Histone modications and alterations lead to changes in
156
M. Kavei et al.
chromosome structure and the positioning or exposure of target sequences to transcription factors, ultimately resulting in the activation or repression of target genes.
The cellular enzyme, which catalyzes histone modication, may transmit the data it
contains to the chromosomal regulator, which ultimately results in a change in the
expression of genes [15].
As previously mentioned, PRC2, through its EZH2 subunit, leads to the trimethylation of H3K27, resulting in the formation of H3K27me3 within the nucleus. At
this stage, PRC1 interacts with H3K27me3 and monoubiquitinates histone H2A at
lysine 119. In this state, chromatin compaction increases, and the transcription of
downstream genes is repressed [16]. One of the important downstream genes in this
pathway is p21, known as a key tumor suppressor gene. This gene inhibits the function of cell cycle CDKs (cyclin-dependent kinases). During its activity, EZH2 binds
to the p21 promoter and, through the modulation of H3K27me3, suppresses the
transcription of the p21 gene, thereby enhancing the cell cycle and cell proliferation
[17]. In some cases, EZH2, in association with PRC2, can methylate non-histone
proteins. The cardiac transcription factor GATA4 is usually methylated at lysine 299
by the telomeraseactivity of EZH2. As a result, the acetylation of GATA4 through
p300 is reduced, leading to the repression of GATA4 expression [4].
EZH2 can also independently activate downstream genes through direct methylation of non-histone proteins, even in the absence of PRC2. For instance, EZH2
can activate STAT3 by methylating its sequence. However, for this process to occur,
EZH2 needs to be phosphorylated, which is carried out by AKT (or protein kinase
B (PKB)) at serine 21 [5]. The role of EZH2in gene activation, independent of
PRC2, was rst reported in castration-resistant prostate cancer. It was revealed that
phosphorylated EZH2 leads to increased expression of the androgen receptor (AR)
transcription factor through a methylation-dependent mechanism. Ultimately, AR
activation results in the upregulation of downstream genes and promotes the proliferation of cancer cells [6]. The most recent research, however, showed that EZH2
might function non-catalytically in castration-resistant prostate cancer cells in a
manner that was independent of PRC2 and methylation. By occupying the AR
gene’s promoter, EZH2 could directly trigger transcription of the gene, which was
unaffected by a compound that inhibits the enzyme EZH2 [7].
7.3 EZH2 Involvement inCancer Progression
Various members of the PcG family, such as EZH2, have signicant inuences on
cancer progression [18]. As previously mentioned, EZH2 regulates the expression
of downstream genes and proteins through both PRC2-dependent and PRC2independent mechanisms involving methylation. These are the fundamental ways
by which it operates and exhibits the numerous roles previously indicated. However,
aberrant expression, such as overexpression, downregulation, and expression loss,
as well as mutations, are linked to the onset, spread, and metastasis of cancer.
Numerous pieces of evidence have demonstrated a signicant role for EZH2in various cancer processes [19]. Interestingly, while many studies have shown its
7 Prostate Cancer andEZH2 Signaling
157
oncogenic role in different cancers, such as breast cancer, gastric cancer, thyroid
carcinoma, and endometrial carcinoma, some research has reported a tumor suppressor role for EZH2.
Additionally, an invivo investigation supports the signicance of EZH2in the
spread of cancer cells [20]. While melanoma-positive lymph nodes and distant lung
metastases often arise in control melanoma model mice, these conditions are signicantly reduced and almost absent in EZH2 conditional knockout mice [21]. The
earliest and crucial step in cell invasion and metastasis is the epithelial- mesenchymal
transition (EMT). Exogenous EZH2 overexpression increased mesenchymal marker
Vimentin expression while decreasing epithelial marker E-cadherin level in an
experiment with pancreatic cancer cells, whereas EZH2 knockdown decreased
Vimentin expression while increasing E-cadherin expression [22]. These ndings
demonstrated EZH2’s potential to induce EMT in pancreatic cancer cells. A signicant factor in tumor metastasis is tumor angiogenesis, and EZH2 is a crucial factor
for this process regulation. The activation of vascular endothelial growth factor
(VEGF) via a paracrine circuit which stimulates angiogenesis by methylating and
silencing vasohibin1 is directly responsible for the rise in endothelial EZH2 [23].
7.4 EZH2 andProstate Cancer Progression
Recent investigations have demonstrated that the expression of EZH2 signicantly
increases in aggressive prostate cancer, thus playing a crucial role in the progression
of prostate cancer. Inhibition or reduction of EZH2 expression leads to cell cycle
arrest. Furthermore, it induces reduced invasiveness and cellular proliferation under
laboratory conditions. Additionally, its downregulation can halt tumor growth
within the body [24–28]. Based on the aforementioned, the oncogenic behaviors of
EZH2 are due to its epigenetic silencing of tumor suppressor genes [29]. Moreover,
studies have indicated that EZH2 has non-histone substrates, including forkhead
box A1 (FOXA1) [30]. EZH2 leads to the methylation of FOXA1, resulting in the
recruitment of deubiquitinase and prevention of FOXA1 degradation, thereby
increasing the protein level of FOXA1 in the cell. Elevated expression of both
FOXA1 and EZH2 is correlated to poor prognosis in patients with prostate cancer.
Furthermore, FOXA1 overexpression makes PCa cells more vulnerable to EZH2
MTase inhibitors that prevent FOXA1 protein degradation. These enzymatic EZH2
inhibitors’ growth-inhibitory effects may be reversed by re-expressing FOXA1.
However, the effectiveness of these enzymatic EZH2 inhibitors in prostate cancer is
often considerably less than what is observed in hematologic malignancies, pointing to the presence of essential EZH2 target genes that are resistant to PRC2 MTase
activity [31]. EZH2 demonstrates an oncogenic activity in polycomb-independent
and androgen-refractory prostate cancer cell lines, involving EZH2’s capacity to
operate as an androgen receptor activator [6].
The operational role of the androgen receptor’s activation depends on the phosphorylation of EZH2. Additionally, the presence of the intact methyltransferase