Page 39 - ARNM-3-1

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

Figure 1. Enhancer of zeste homolog 2 (EZH2) and AT-rich interactive domain 1A (ARID1A) synthetic lethality. Synthetic lethality is due to antagonistic
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roles played by methyltransferase EZH2 and chromatin remodeler SWI-like gene ARID1A, in regulating target gene PIK3IP1. In the context of ARID1A
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mutation, PIK3IP1 is upregulated by EZH2 inhibition and contributes to synthetic lethality by inhibiting PI3K/AKT signaling. Created in BioRender by
Lukas, L. (https://BioRender.com/y06c279).
silencing of tumor suppressor genes, such as RUNX3, 16,26 to be more sensitive to doxorubin, simultaneous
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FOXC1 in luminal B breast cancer, 16,27 FOXO3, 16,28,29 , and delivery of EZH2-targeting siRNA by vortex magnetic
CDKN1c, also known as p57. 16,28,30 In TNBC, EZH2- nanorods – potentially increasing FOXC1 expression –
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mediated H3K27me3 gene silencing includes repression synergistically improved doxorubicin efficacy in TNBC.
of TIMP2 transcription, resulting in increased activity of Although EZH2-mediated silencing of genes is the typical
matrix metalloproteinase 2 and matrix metalloproteinase mechanism of the PRC2 complex, H3K27me3 can also
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9, which enhances the invasive capacity of TNBC cells. be associated with transcriptional upregulation. EZH2
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EZH2 also suppresses the epithelial-mesenchymal promotes KRT14 transcription by attenuating the binding
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transition suppressor gene CDH1. In addition, EZH2- of repressor SP1 to its promoter, thereby facilitating TNBC
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mediated epigenetic inactivation of FOSB promotes TNBC migration, invasion, and peritoneal metastasis. Examples
cell proliferation by inactivating the p53 pathway. EZH2 of EZH2-mediated H3K27me3 transcriptional silencing in
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accelerates cell invasion through transcriptional silencing TNBC are shown in Figure 2.
of the metastasis suppressor Raf-1 kinase inhibitor Beyond its H3K27me3-mediated effects on gene
protein. Overexpression of EZH2 increases the level of transcription through its role within the PRC2 complex,
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H3K27me3 and inhibits expression of FOXC1. Although EZH2 has also been identified as a transcriptional activator
TNBC cell lines with low FOXC1 expression were reported of several genes. 36,37 In TNBC, these non-canonical effects
Volume 3 Issue 1 (2025) 31 doi: 10.36922/arnm.5132