Page 40 - ARNM-3-1

Advances in Radiotherapy
& Nuclear Medicine EZH2 inhibition in ARID1A-deficient TNBC

Figure 2. Enhancer of zeste homolog 2 (EZH2)-mediated H3K27me3 gene transcription. The polycomb repressive complex 2 complex consists of the
core proteins EZH2, embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and retinoblastoma binding protein 4 and 7 (RBBP4/7).
122
Gene silencing in triple-negative breast cancer (TNBC) through EZH2-mediated H3K27me3 includes repression of tissue inhibitor of metalloproteinase
2 (TIMP2) transcription, which results in increased activity of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) with a
subsequent increased invasive activity of TNBC cells. EZH2 suppresses epithelial-mesenchymal transition suppressor gene CDH1. EZH2-mediated
31
22
epigenetic inactivation of FOSB promotes TNBC cell proliferation by inactivating the p53 pathway. EZH2 accelerates cell invasion, at least in part,
32
through transcriptional repression of the metastasis suppressor Raf-1 kinase inhibitor protein (RKIP). EZH2 promotes keratin-14 (KRT14) transcription
31
by attenuating the binding of repressor SP1 to its promoter, which promotes TNBC migration, invasion, and peritoneal metastasis. Overexpression of
35
EZH2 increases the level of H3K27me3 and inhibits the expression of forkhead box C1 (FOXC1). Created in BioRender by Lukas, L (https://BioRender.
33
com/q82a381).
include interaction with RelA/p65 and RelB subunits of and metastasis and found that tazemetostat significantly
nuclear factor-kappa B to activate the transcription of inhibited the migration and invasion of TNBC cells
cytokines, such as TNF and IL6. 36,37 EZH2’s transcriptional in vitro. Furthermore, in vivo experiments demonstrated
activation of RelB in TNBC has been shown to contribute that tazemetostat treatment led to a marked reduction
to the maintenance of tumor-initiating cells. It is in peritoneal metastasis in mouse models, indicating its
36
hypothesized that EZH2 promotes breast cancer stem potential to suppress metastatic spread in solid tumors. A
35
cells through the methylation and activation of STAT3. phase II study of Tazemetostat in solid tumors harboring
36
EZH2 has been found to suppress the expression of an ARID1A mutation is currently enrolling participants
transcription factor GATA3 and pro-apoptotic BH3-only (NCT05023655).
protein BMF, thereby protecting TNBC cells from luminal Enhancers of zeste homolog 2 inhibitors, such as
differentiation and cell death. Gonzalez et al. identified tazemetostat, do not affect the intrinsic protein stability
24
38
reciprocal mechanistic cooperation between EZH2 and of EZH2, but instead affect the catalytic ability of EZH2
p38α, which promotes the growth and metastasis of by competing with the cofactor SAM and binding to
TNBC. EZH2 methylates p38a, increasing its protein the SET domain of EZH2. However, in most solid
24
42
stability and activity in TNBC. This finding demonstrates tumors, the EZH2 protein itself, in addition to its role in
24
that EZH2 functions not only through H3K27me3- H3K27me3-dependent growth and proliferation, is also
mediated transcriptional silencing but also through direct involved in tumor proliferation. Consequently, while
42
methylation of the protein p38a. 24 EZH2 inhibitors have shown efficacy in certain malignant
Tazemetostat, an EZH2 inhibitor that blocks the blood tumors, their effectiveness against solid tumors such
methyltransferase activity by competing with the methyl as TNBC remains limited. To block the proliferation of
42
donor S-adenosyl-L-methionine (SAM), was FDA- TNBC cells and inhibit primary tumor growth, it may
39
approved for the treatment of epithelioid sarcoma and be necessary to reduce EZH2 protein levels rather than
follicular lymphoma. 40,41 However, despite its efficacy solely inhibit its methyltransferase activity. Wang et al.
43
42
in preventing therapy relapse in lymphomas, other found that although EZH2 is over-expressed in TNBC
clinical trials showed minimal impact of treatment with cells compared to normal breast cells, the anti-proliferative
tazemetostat and other catalytic inhibitors on solid effect of EZH2 inhibitors on TNBC cells was minimal.
42
tumors. One notable study by Verma et al. specifically While these inhibitors can effectively reduce H3K27me3
42
35
evaluated the impact of tazemetostat on TNBC migration repressive marks, they do not inhibit the proliferation
Volume 3 Issue 1 (2025) 32 doi: 10.36922/arnm.5132