Page 60 - Read Online

Page 4 of 16 Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05

Figure 2. Histone methyltransferase activity of EZH2/PRC2 is part of a sequence of epigenetic alterations that lead to condensation of
chromatin into tightly bound structures, thereby physically preventing access to transcription factors and other transcriptional
machineries.

mutations have promising initial results . However, mutations of EZH2 are not prevalent in soft tissue
[14]
sarcomas. A study in 2012 screened a range of sarcoma types for mutations in a selection of seven genes,
including EZH2, known to be recurrently mutated in non-sarcomatous cancers. Of these genes only two
PIK3CA mutations and one JAK mutation were observed in the entire cohort of samples (3/108; 2.8%). The
soft tissue sarcomas investigated in that study included malignant fibrous histiocytomas,
rhabdomyosarcomas, malignant peripheral nerve sheath tumours, leiomyosarcomas, synovial sarcomas,
liposarcomas, angiosarcomas, and Ewing sarcomas .
[15]

Rather, EZH2 is overexpressed in many STS in comparison to normal tissue, which may be attributed to the
cell of origin of these tumours. STS are thought to be derived from mesenchymal stem cells, where the
balance of EZH2 expression along with other histone modifying enzymes is thought to control the
differentiation lineage process [16-19] . The reason why overexpression of wildtype EZH2 leads to associated
poor outcomes can primarily be understood in terms of the normal function of EZH2. EZH2 is involved in
silencing genes which drive differentiation in developing cells/tissues . Under normal development, EZH2
[20]
expression fades over time, to become almost undetectable in adult specialized cells and tissues [Figure 3
] . The inappropriately timed expression of EZH2 is therefore thought to lead to an undifferentiated
[10]
phenotype with cells maintaining the ability for self-renewal.

Of increasing importance and focus are interactions between PRC2 and SWItch/Sucrose Non-Fermentable
(SWI/SNF) complex. The latter is another chromatin remodelling machinery with an opposed function to
PRC2 . The antagonistic mode of action of both complexes is essential to ensuring homeostasis and proper
[10]
epigenetic profile of the cells. Mutations in the SWI/SNF complex subunit SMARCB1 (also referred to as
INI1) result in loss of SMARCB1 regulatory function, leading to the dysregulation of EZH2 activity and thus
abnormal gene repression and oncogenic capacity of EZH2 [21-23] . As a consequence, it is observed as
development and progression of solid tumours . Nonetheless, the EZH2 aberration linked to SWI/SNF
[24]