namely mithramycin, DZNep, and paclitaxel, are used to study the effects of
targeting this MT in cancer cells [23].
1.3 The H3K9 Methyltransferases SUV39H1 and SUV39H2
SUV39H1 was the first histone lysine methyltransferase to be discovered. SUV39H1
and SUV39H2 catalyze, via a SAM-dependent mechanism, H3K9 dimethylation
(me2) and trimethylation (me3) by preferentially binding to monomethylated (me1)
H3K9 [24, 25]. Both enzymes are crucial in several biologically relevant processes
[26]. For example, SUV39H1/2 may serve as a tumor suppressor by maintaining the
H3K9 trimethylation mark at pericentric heterochromatin [27]. SUV39 knockdown
induces higher sensitivity of tumor cells to radiation or chemotherapy agents, while
their overexpression promotes malignancy and resistance to these treatments
[28]. Furthermore, SUV39H2 might be involved in maintaining HIV silencing
[29]. To date, only one SUV39 inhibitor has been published chaetocin (8, Fig. 1),
that is, a potent SAM-competitive inhibitor with an IC 50 of 0.6 μM [30]. However,
follow-up studies have demonstrated that compound 8 is not very selective [18, 31]
as it acts also on EHMT1 and EHMT2 and other targets such as thioredoxin
[32]. Nevertheless, when used for AML treatment, compound 8 has been proven
to induce apoptosis and to reduce cancer progression in vivo, similar to loss of
SUV39H1 alone [32]. However, as off-target effect, upregulation of reactive oxygen
species is also believed to be responsible for the response to chaetocin treatment
[32]. To date, no small synthetic selective SUV39 inhibitor is known in the literature,
underlying the need of the discovery of new specific hit compounds for this target.
1.4 The H3K27 Methyltransferases EZH1 and EZH2
The lysine methyltransferases EZH1 or EZH2 constitute the catalytic subunit of the
PRC2 complex. Even though EZH1 and EZH2 possess a high sequence similarity,
they exhibit different catalytic efficiencies, distinct chromatin binding properties, and
expression patterns [33]. By themselves, EZH1 and EZH2 are not able to catalyze
H3K27 methylation, but they require the copresence of at least two other protein
subunits in the complex: EED and SUZ12 [34]. EZH2 has been proved to have also
PRC2-independent functions, being involved in the methylation of a number of
nonhistone substrates, such as the transcription factors GATA4 and PLZF [35]. The
non-PRC2 activity of EZH2 could drive to transcriptional activation, rather than
repression [36]. The polycomb complex is involved in the regulation of different
functions in addition to the HOX gene silencing including X-chromosome inactivation, germline development, cell fate decision, cell-cycle regulation, senescence,
stem cell pluripotency, and cancer metastasis [37]. In humans, the self-renewal ability
of embryonic and tissue-specific stem cells is maintained by the PRC2 activity, and its
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G. Stazi et al.
targeting this MT in cancer cells [23].
1.3 The H3K9 Methyltransferases SUV39H1 and SUV39H2
SUV39H1 was the first histone lysine methyltransferase to be discovered. SUV39H1
and SUV39H2 catalyze, via a SAM-dependent mechanism, H3K9 dimethylation
(me2) and trimethylation (me3) by preferentially binding to monomethylated (me1)
H3K9 [24, 25]. Both enzymes are crucial in several biologically relevant processes
[26]. For example, SUV39H1/2 may serve as a tumor suppressor by maintaining the
H3K9 trimethylation mark at pericentric heterochromatin [27]. SUV39 knockdown
induces higher sensitivity of tumor cells to radiation or chemotherapy agents, while
their overexpression promotes malignancy and resistance to these treatments
[28]. Furthermore, SUV39H2 might be involved in maintaining HIV silencing
[29]. To date, only one SUV39 inhibitor has been published chaetocin (8, Fig. 1),
that is, a potent SAM-competitive inhibitor with an IC 50 of 0.6 μM [30]. However,
follow-up studies have demonstrated that compound 8 is not very selective [18, 31]
as it acts also on EHMT1 and EHMT2 and other targets such as thioredoxin
[32]. Nevertheless, when used for AML treatment, compound 8 has been proven
to induce apoptosis and to reduce cancer progression in vivo, similar to loss of
SUV39H1 alone [32]. However, as off-target effect, upregulation of reactive oxygen
species is also believed to be responsible for the response to chaetocin treatment
[32]. To date, no small synthetic selective SUV39 inhibitor is known in the literature,
underlying the need of the discovery of new specific hit compounds for this target.
1.4 The H3K27 Methyltransferases EZH1 and EZH2
The lysine methyltransferases EZH1 or EZH2 constitute the catalytic subunit of the
PRC2 complex. Even though EZH1 and EZH2 possess a high sequence similarity,
they exhibit different catalytic efficiencies, distinct chromatin binding properties, and
expression patterns [33]. By themselves, EZH1 and EZH2 are not able to catalyze
H3K27 methylation, but they require the copresence of at least two other protein
subunits in the complex: EED and SUZ12 [34]. EZH2 has been proved to have also
PRC2-independent functions, being involved in the methylation of a number of
nonhistone substrates, such as the transcription factors GATA4 and PLZF [35]. The
non-PRC2 activity of EZH2 could drive to transcriptional activation, rather than
repression [36]. The polycomb complex is involved in the regulation of different
functions in addition to the HOX gene silencing including X-chromosome inactivation, germline development, cell fate decision, cell-cycle regulation, senescence,
stem cell pluripotency, and cancer metastasis [37]. In humans, the self-renewal ability
of embryonic and tissue-specific stem cells is maintained by the PRC2 activity, and its
130
G. Stazi et al.