4.2 The Chromodomain
4.2.1 Chromodomain Structure and Function
Chromodomains are a highly conserved family of methyllysine reader domains that play
diverse roles in gene repression/expression in cellular differentiation, cancer progression, and stem cell maintenance [61, 64, 65]. Named after “chromatin organization
modifier,” the chromodomain was originally identified in D. melanogaster proteins
HP1 (heterochromatin-associated protein 1) and Polycomb, contributing to genomic
imprinting [66]. The chromodomain of HP1, which binds histone H3K9me3, was
the first methyllysine reader domain to be discovered [16, 17].
Made up 40–60 amino acid residues, the canonical chromodomain structure is
a monomeric three-stranded antiparallel β-sheet flanked by a C-terminal alpha
helix [67]. Chromodomains can be generally divided into three structurally distinct
classes: the HP1 family, the Polycomb group (PcG) family, and the chromo-ATPase/
helicase-DNA-binding (CHD) family [68].
4.2.2 Small Molecules Targeting Chromodomains
4.2.2.1 Targeting CBX7
The members of the Polycomb group of CBX proteins (CBX2, CBX4, CBX6,
CBX7, and CBX8) compete with each other for incorporation into multiprotein
Polycomb-repressive complexes (PRCs) of which two main complexes are present
in mammals (PRC1 and PRC2). Members of the PRC are frequently prone to
dysregulation. Representing transcriptional repressors, Polycomb group genes
are implemented in development, stem cell maintenance, and cancer progression
[69, 70]. Each of the five human CBX proteins recognizes and binds to H3K27me3
(with a different degree of selectivity; see above), a mark that is created by another
member of the PRC, the lysine methyltransferase EZH2/KMT6 [71, 72].
CBX7 is among the best-studied representatives of the Polycomb paralogs. It is
a master controller that extends cellular lifespan, delays senescence, drives proliferation, and bestows pluripotency to adult and embryonic stem cells [73, 74]. Multiple
lines of evidence suggest promise for CBX7 as a therapeutic target in certain forms
of cancer. CBX7 expression is strongly proliferative in various stem cell and
stemlike cancer cell lines [71, 73, 75, 76]. It has been observed that the depletion
or knockdown of CBX7 in prostate cancer cell lines induces a senescent phenotype
with reduced cell proliferation [73], whereas CBX7 expression significantly
increases in clinical samples of hormone-resistant prostate cancer relative to
hormone-dependent prostate cancers [77] and is linked to poor prognosis in ovarian
clear cell adenocarcinoma [76]. Additional malignancies, where CBX7 seems to
play a central role, are lymphomas [78] and T-cell leukemias [70]. Therefore, even
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G. Sbardella
4.2.1 Chromodomain Structure and Function
Chromodomains are a highly conserved family of methyllysine reader domains that play
diverse roles in gene repression/expression in cellular differentiation, cancer progression, and stem cell maintenance [61, 64, 65]. Named after “chromatin organization
modifier,” the chromodomain was originally identified in D. melanogaster proteins
HP1 (heterochromatin-associated protein 1) and Polycomb, contributing to genomic
imprinting [66]. The chromodomain of HP1, which binds histone H3K9me3, was
the first methyllysine reader domain to be discovered [16, 17].
Made up 40–60 amino acid residues, the canonical chromodomain structure is
a monomeric three-stranded antiparallel β-sheet flanked by a C-terminal alpha
helix [67]. Chromodomains can be generally divided into three structurally distinct
classes: the HP1 family, the Polycomb group (PcG) family, and the chromo-ATPase/
helicase-DNA-binding (CHD) family [68].
4.2.2 Small Molecules Targeting Chromodomains
4.2.2.1 Targeting CBX7
The members of the Polycomb group of CBX proteins (CBX2, CBX4, CBX6,
CBX7, and CBX8) compete with each other for incorporation into multiprotein
Polycomb-repressive complexes (PRCs) of which two main complexes are present
in mammals (PRC1 and PRC2). Members of the PRC are frequently prone to
dysregulation. Representing transcriptional repressors, Polycomb group genes
are implemented in development, stem cell maintenance, and cancer progression
[69, 70]. Each of the five human CBX proteins recognizes and binds to H3K27me3
(with a different degree of selectivity; see above), a mark that is created by another
member of the PRC, the lysine methyltransferase EZH2/KMT6 [71, 72].
CBX7 is among the best-studied representatives of the Polycomb paralogs. It is
a master controller that extends cellular lifespan, delays senescence, drives proliferation, and bestows pluripotency to adult and embryonic stem cells [73, 74]. Multiple
lines of evidence suggest promise for CBX7 as a therapeutic target in certain forms
of cancer. CBX7 expression is strongly proliferative in various stem cell and
stemlike cancer cell lines [71, 73, 75, 76]. It has been observed that the depletion
or knockdown of CBX7 in prostate cancer cell lines induces a senescent phenotype
with reduced cell proliferation [73], whereas CBX7 expression significantly
increases in clinical samples of hormone-resistant prostate cancer relative to
hormone-dependent prostate cancers [77] and is linked to poor prognosis in ovarian
clear cell adenocarcinoma [76]. Additional malignancies, where CBX7 seems to
play a central role, are lymphomas [78] and T-cell leukemias [70]. Therefore, even
350
G. Sbardella