Page 68 - Read Online

Page 12 of 16 Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05

and the transcription factor, interferon regulatory factor 1 in hepatocellular carcinoma (HCC) cells and
clinical samples. The authors posited that an EZH2 inhibitor may therefore improve responses to anti-PD-
1/PD-L1 therapy.

In short, EZH2 as a treatment target will certainly be of use in immune therapies; however, due to its role in
both normal and abnormal immune processes it is likely that its efficacy will be sub-type/genotype
dependant, highlighting the need for studies into this potential combination for the treatment of STS.

CONCLUSIONS
This review has evaluated EZH2 as a potential target in treatment of STS, an exceptionally diverse group of
malignancies, with various underlying genetic and epigenetic alterations defining their development, clinical
behaviour and responsiveness to therapies. However, one limitation of this review is that many STS have yet
to be studied in the context of EZH2. There are over 60 distinct histological subtypes of STS, for many of
which we have not yet understood the contribution of EZH2 or how it may be exploited for therapeutic
benefit. Table 2 summarises the main findings of this review.

STS reviewed in this study almost ubiquitously express high levels of EZH2. As there is no evidence of
genetic aberration of EZH2 that might be contributing to this overexpression, it is highly likely that this is
the result of the undifferentiated nature of STS, whereby STS cells retain hallmarks of their likely cell of
origin, a mesenchymal stem cell. For certain STS, the genetic hallmark of SMI/SNF deregulation,
exemplified by SMARCB1 deficiency seen in SS, is likely contributing to the aberrant activity of PRC2
[52]
driven by EZH2, which in turn is thought to predispose tumour cells to sensitivity to EZH2 inhibition .
Indeed, in SS the majority of the cases exhibit lack of SMARCB1 protein as well as the presence of SS18-SSX
translocation, which is thought to make cells more prone to EZH2 inhibition.

The correlation of EZH2 protein expression with clinical features of STS is not consistent across studies.
However, the most common trend seen includes highly enhanced levels of protein in malignant tumour/cell
lines and metastatic lesions, as compared to benign tumour or healthy tissue. The highest divergence arose
among EZH2 overexpression with regard to histological grade and clinical stage of the tumours, suggesting
either limited sample size or patient/tumour specific EZH2 expression in each phase of the disease.

This study has highlighted both similarities and differences in EZH2 expression and response to EZH2
modulation across STS subtypes. Each STS type has a differing cell lineage type, leading to differing genetic
and epigenetic diversity both between STS types and even within STS subtypes. As a consequence, this may
explain differences in response to EZH2 modulation as subset of genes that are both targeting and are
targeted by PRC2/EZH2 are likely to be typical to that cell type. This may therefore also have implications in
the use of EZH2 inhibitors as therapeutics and thus differing combinations with EZH2 inhibitors need to be
investigated for different STS.

The results of pharmacological and genetic inhibition of EZH2 seem to be highly promising as a therapeutic
option for STS. One key aspect is inhibitor specificity. DZNep is the least specific for EZH2 as its mode of
action is inhibition of S-adenosylhomocysteine hydrolase and therefore also inhibits the activity of other
[82]
methyltransferases . Conversely, tazemetostat has been shown to be highly potent and selective for
[52]
EZH2 . Worth noting is the fact that combined treatment of specific EZH2 inhibitors either with
differentiating agents, other epigenetic agents or chemotherapeutics resulted in enhanced anti-tumour
activity in many STS studies. A number of STS are predominantly associated with paediatric onset and thus
strategic combination of EZH2 targeted inhibitors with standard of care therapies will likely be the most