Page 67 - Read Online

Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05 Page 11 of 16

THE MECHANISM OF ACTION OF EZH2 IN STS
It must be emphasized that EZH2 is a ubiquitous and multifaceted enzyme, involved in numerous
regulatory axis and molecular networks, including those promoting oncogenesis. Vella and colleagues
demonstrated in ERMS that the levels of a number of miRNAs were restored as EZH2 levels decreased,
resulting in anti-cancer activity. Furthermore, depletion or inhibition of EZH2 was highly correlated with
altered cell cycle and reduction of expression of several proteins, such as Ki-67 or TBX3 in RMS. However,
the role of EZH2 should be considered differently depending on the cellular context: it can serve as a
transcriptional suppressor and a transcriptional co-activator [65,66] . Previous research has shown that EZH2
may act in noncanonical manner, independently of PRC2 and its histone methyltransferase function,
activating the downstream genes through non-histone targets methylation or direct binding to proteins in
several cancer types [67-70] . Additionally, the PRC2-SWI/SNF interactions are essential in the regulation of
gene expression in several signalling pathways, such as RB, Cyclin D1, MYC and hedgehog, which are
impaired in many cancer types . In the presented results, EZH2 depletion led to decreased activity of the
[6]
[39]
oncogenic molecules such as E2F and c-Myc involved in signal transduction pathways , proposing indirect
implications of EZH2 to oncogenesis. When interpreting the outcomes, there is also a need for
contextualizing these with relation to the tumour microenvironment (TME), which consists not only of
cancer cells but also of extracellular matrix, fibroblasts, adipocytes, endothelia, and immunomodulators
such as T and NK cells, tumour-associated macrophages and dendritic cells. All of these play an essential
[71]
role in the overall response to the therapy and contribute to tumour resistance . Furthermore, the diversity
and number of reactions within the TME may promote cancer escape from immune vigilance . Having
[72]
said this, the complexity of TME may be one of the main reasons for the diverse results among different STS
and even within the same histology. Another likely explanation may be heterogenous character of STS,
various kinetics and attributes of the cell lines or xenografts, specificity of the inhibitor used and underlying
genetic alterations.

The role of PRC2/EZH2 in the immune response - a potential combination therapy?
The involvement of PRC2/EZH2 in the immune response is a burgeoning area of research that has
implications for both immune-based therapy efficacy and use of EZH2 inhibition as a treatment itself.
Immune therapy is not yet a common modality in STS; however, combination therapies utilising EZH2
inhibition and immune therapies may prove to be an effective treatment for STS.

PRC2/EZH2 has been shown to be involved in normal haematopoiesis, the regulation of immune cells, and
is essential for T-cell proliferation and anti-tumour immunity [73-76] . Conversely it is also implicated in some
haematological malignancies [77,78] . One potential complication of using EZH2 inhibitors as single agents is
unintended effects upon the immune environment. A paper by Huang and colleagues in 2019 identified that
in immune-competent mice treated with GSK126, the anti-tumour effects of EZH2 inhibition were reduced
compared to immune-deficient mice . Importantly the authors also described increased production of
[79]
myeloid derived suppressor cells (MDSCs) in the GSK126 treated, immune-competent mice, potentially
leading to an immune suppressive microenvironment. The authors suggest this as a mechanism behind
some of the poorer trial results seen with GSK126.

On the other hand, there is evidence that inhibition of EZH2 may help to improve anti-tumour responses to
specific immune check point inhibitors. For example, CPI1205 has been shown to improve the efficacy of
the anti-CTLA4 treatment, ipilimumab in a mouse model, primarily by compensating for an increased level
of EZH2 induced by ipilimumab itself. The addition of CPI1205 was found to modulate cytotoxic T cells
and phenotypically alter Tregs into effector-like T cells and improve the immune response . Furthermore,
[80]
[81]
Xiao et al. (2019) showed that in vitro EZH2 negatively regulated the expression of both PD-L1 (CD274)