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Page 2 of 16 Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05

INTRODUCTION
Soft tissue sarcomas (STS) constitute a highly heterogenous group of rare malignancies believed to be of
mesenchymal origin. Mesenchymal stem cells harbour powerful self-renewal capacity and multi-lineage
differentiation potential into various tissues, such as adipose, muscle, bone and cartilage. Over 60 distinct
STS subtypes have been identified with regard to their biological features and clinical manifestation, making
the classification of these tumours often problematic and challenging. STS can occur in any part of the body,
but the most frequent sites include the extremities, head and neck areas as well as trunk. STS comprise
around 1% of all adult cancers and around 8% of all paediatric and adolescent tumours. However, the
spectrum of STS subtypes differs in these different age ranges. Despite being relatively rare cancers, the vast
majority of diagnosed cases of STS present with highly aggressive behaviour, poor prognosis and advanced
stage of the disease at point of detection. Many STS can be thought of as undifferentiated tumours, where
STS cells express early markers of lineage-specific differentiation but do not differentiate into the mature,
benign tissue type. For example, rhabdomyosarcomas (RMS) resemble immature skeletal muscle cells that
have failed to complete differentiation and cell cycle arrest, and the restoration of this process is considered
[1,2]
to be of therapeutic value .
A number of STS discussed in this review, harbour specific genetic hallmarks, such as chromosome
translocations and specific gene mutations or amplification events. These contribute to the process of
oncogenesis and may be useful diagnostic features. An example is the recurrent chromosomal translocation
t (X;18) (p11.2;q11.12) found in synovial sarcomas (SS), leading to gene fusions between SS18 on
chromosome 18 and either SSX1, SSX2 or in rare cases SSX4 on chromosome X. The abnormal fusion
protein SS18-SSX disrupts the epigenetic regulation of gene expression and is believed to drive sarcoma
[3,4]
formation in SS . Another example is malignant peripheral nerve sheath tumours (MPNSTs), in which
Neurofibromin (NF1) tumour suppressor gene mutations are thought to drive malignancy in some patients.
Such mutations lead to inactivation of NF1 protein and therefore to development and pathogenesis of
MPNSTs . The same holds true for extremely rare and aggressive atypical teratoid rhabdoid tumours
[5]
(ATRTs, brain) or malignant rhabdoid tumours (MRTs, kidneys and soft tissues) where homozygous
inactivation of SMARCB1, and resultant deficiency of SMARCB1 protein, a member of the SWI/SNF
complex, occur in the majority of these malignancies . RMS, ATRT and MRT tumours affect
[6]
predominantly infants and/or children/adolescents, with RMS being the most frequent, accounting for 50%
of all STS in childhood .
[2,7]

Current treatment of STS is largely based on tumour resection followed by chemotherapy and/or
radiotherapy. This multimodal approach often leads to long-term side effects and, due to resistance to
cytotoxic agents in large proportion of sarcoma patients, it also results in local recurrence as well as
metastasis. Despite intensification of treatment regimes, little significant advancement in treatment
outcomes for high-risk patients with these malignancies has been noted in recent years . The low
[8]
efficiency/failure of the standard therapies in STS highlights a fundamental necessity for development of
novel, more effective and less harmful treatment strategies for sarcoma patients.

ROLE OF EZH2 IN STS
Enhancer of Zeste Homologue 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2
(PRC2), a multiprotein complex comprised of four core units, EED, SUZ12, RbBP4, and EZH2, although a
[9]
number of other auxiliary proteins have also been shown to modulate PRC2 activity [Figure 1] . PRC2 is
crucial for maintaining the epigenetic state of the cells through modulation of chromatin structure and by
such means, regulation of gene expression. EZH2 is a histone methyltransferase whose mode of action is
observed as addition of methyl groups at lysine 27 in histone H3 through its active SET domain motif,