Histone demethylation enzymes and dynamic cell biology Leanne Stalker 1 and Christopher Wynder 2,3 1 -Department of Biomedical Science,,University of Guelph, 2 -Department of Biochemistry, University of Western Ontario, 3 PTM Discoveries, London Ontario Introduction In order to maintain structure and organization within the nucleus of a eukaryotic cell, the large DNA macromolecule is structured in to chromosomes. To provide an additional layer of organization, these chromosomes are wrapped around protein complexes containing proteins known as histones to form the basic unit of chromatin, the nucleosome (Kornberg, 1974; Kornberg & Lorch, 1999). Each nucleosome is comprised of an octameric core containing two each of Histone H2A, H2B, H3 and H4 around which 146bp of DNA is wound. This DNA is then secured to the core by an additional histone, histone H1(Kornberg & Lorch, 1999; Kouzarides, 2007; Sims et al, 2003; Volkel & Angrand, 2007). This DNA/protein complex provides a mechanism by which to conform the large DNA
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Histone demethylation enzymes and dynamic cell biology
Leanne Stalker1 and Christopher Wynder2,3
1-Department of Biomedical Science,,University of Guelph, 2-Department of Biochemistry, University of Western Ontario, 3PTM Discoveries, London Ontario
Introduction
In order to maintain structure and organization within the nucleus of a
eukaryotic cell, the large DNA macromolecule is structured in to
chromosomes. To provide an additional layer of organization, these
chromosomes are wrapped around protein complexes containing proteins
known as histones to form the basic unit of chromatin, the nucleosome
(Kornberg, 1974; Kornberg & Lorch, 1999). Each nucleosome is comprised
of an octameric core containing two each of Histone H2A, H2B, H3 and H4
around which 146bp of DNA is wound. This DNA is then secured to the
core by an additional histone, histone H1(Kornberg & Lorch, 1999;
Kouzarides, 2007; Sims et al, 2003; Volkel & Angrand, 2007). This
DNA/protein complex provides a mechanism by which to conform the large
DNA molecule to the confined space of the nucleus, allows protection from
DNA damage during cell division, and plays a pertinent role in
transcriptional regulation(Kooistra & Helin, 2012; Kouzarides, 2007). Each
individual histone protein contains two highly conserved protein domains
including a large globular core and an amino terminal tail that protrudes
from both the histone individually and the nucleosomal structure as a
whole(Luger et al, 1997). From a gene regulation perspective, these N-
terminal tails represent an infinite ability for the nucleosomal structure to
become modified.
Histone tail modifications
Due to their availability outside of the core nucleosome, many amino
acid residues on histone tails are targets of extensive post transcriptional
modifications. These occur on specific amino acid residues and include
acetylations, phosphorylations, SUMOylations, ubiquitinations and
methylations. The result of the addition of these molecular groups is
varied and depends highly on both the specific amino acid modified and
the modification itself (Kouzarides, 2007). The addition of these various
groups tends to result in one of two possible consequences. First, it may
change the interaction between DNA and the histone directly leading to an
alteration of the chromatin structure as a whole. This activity is observed
mostly when a posttranscriptional modification, such as an acetylation,
alters the charge of an amino acid on the histone tail. Acetylation of a
lysine (K) residue acts to neutralize its basic charge. This loosens the
interaction between the histone and DNA, increasing the accessibility of
the DNA and generally resulting in transcriptional activation(Shogren-
Knaak et al, 2006; Workman & Kingston, 1998). Acetylation is the most
extensively studied of the post-transcriptional modifications and occurs
most frequently on residues K9, K14, K18 and K56 of Histone H3. The
enzymes responsible for both the addition of the acetyl group, Histone
Aceytl Transferases (HATs) and the enzymes responsible for the removal
of the acetyl group, Histone Deacetylases (HDACs) have been increasingly
popular targets for drug discovery(Khan & Khan, 2010; Kuo & Allis, 1998).
The second consequence of histone modification is the alteration of
non-histone protein recruitment to histone tails. For example, histone
phosphorylating enzymes MSK1/2 and RSK2 tend to target serine residues
at H3S10. Phosphorylation of this residue is found to attract the phospho-
binding protein 14-3-3, which is thought to activate NFB-regulated
gene alterations in patient samples of ccRCC, had provided evidence that
mutations to KDM5c were higher than would be expected by chance in
ccRCC patients (Dalgliesh et al, 2010), suggesting a connection between
KDM5c alterations and aberrant levels of H3K4me3. Niu et al. have shown
that KDM5c is responsible for suppressing HIF response genes by removal
of H3K4me3, and that mutations to KDM5c are promote tumour growth.
This tumour suppressor role of KDM5c is specific to this family member as
loss of KDM5c (but not KDM5a or KDM5b) abolished the difference between
VHL-/- and +/+ tumors (Niu et al, 2012).
Given their role in stem cell biology and development, we
are left to question whether KDM5s simply do the “right” job at the “wrong”
time in cancers; exerting control similar to non-pathogenic contexts during
differentiation and development, but with aberrant results within a fully
developed tissue. The roles of KDM5s during carcinogenesis appear to
focus on helping tumour cells to survive in contexts when appropriate
cellular signaling would lead to cell death; survival of hypoxia, escaping
apoptosis, increasing potential for invasion, and alterations to cell cycle
leading to over proliferation and the development of inappropriate cell
types. However, information on the roles of these proteins are often
contradictory, with several being classified as proteins with both
oncogenic and tumour suppressor abilities depending on cellular context.
Though, as previously mentioned, reduced H3K4 methylation levels appear
to be linked to poor prognosis in cancer patients (Seligson et al, 2005), in
the case presented above, increased H3K4 in the context of HIF response
genes in ccRCC appears to be tumour-promoting. This again draws
attention to the fine balance of H3K4me3 expression and the regulation of
the enzymes that control this methylation, both are highly dependent upon
cellular context.
KDM5s in tumour sub populations
Several groups have now suggested that KDM5 family
members exert control in specific subsets of a tumour population to
maintain or promote growth. Sharma et al. noted a population of
“reversibly drug tolerant” cells within several human cancers which
maintain viability through an altered chromatin state requiring KDM5a.
These cells appear absolutely required to protect tumors from eradication
(Sharma et al, 2010). Roesch et al. show another angle of the KDM5 cancer
story, using the expression of KDM5b as a biomarker to flag a small
population of slow cycling cells within the heterogeneous population of a
melanoma (Roesch et al, 2010). These “slow” cells appear to be required
for tumour maintenance, giving rise to progeny which express low levels of
KDM5b, and knock down of KDM5b results in an exhaustion of tumour
growth. Interestingly the same group has also proposed that KDM5b has a
tumour suppressor role (Roesch et al, 2006; Roesch et al, 2008). It has
been suggested that the acceleration of cell cycle in these melanocytes
after KDM5b expression decrease may be due to a derepression of E2F-
target genes, thus accelerating cell cycle. Both KDM5b and KDM5a have
been shown to be members of the Rb repression complex, required for the
repression of E2F target genes during senescence (Chicas et al, 2012;
Nijwening et al, 2011). Though repression of E2F targets would generally be
considered a tumour suppressive function, mutations to Rb are common in
cancer progression, allowing pro-proliferative effects to override normal
suppression and could lead to increased oncogenic potential. Following in
this theory, loss of KDM5a in a pRb defective tumour context promotes
senescence and differentiation, suggestive of an oncogenic role in the
absence of Rb (Lin et al, 2011). As noted by Chicas et al., this highlights
the context- dependent role of these demethylases (Chicas et al, 2012).
These results together suggest that though they are involved in
oncogenesis, KDM5s appear to exert their “tumourogenic potential” in
different ways, depending on cellular context and may respond differently
depending on which upstream cellular cues become activated (Figure 3).
These aspects of KDM5 demethylases, though complex,
make them potentially lucrative targets for pharmaceutical intervention.
Enzymes are known to provide excellent drug targets and KDM5b in
particular, due to its low expression level in most adult human tissues, may
provide a potentially safe target for pharmaceuticals. Immunotherapy
approaches against KDM5b have been investigated recently with results
suggesting that KDM5b may represent a tumour associated antigen (TAA)
for breast cancer (Coleman et al, 2010).
The major question that remains for future clinical use of
KDM5 targeting therapeutics is: How can we utilize this knowledge of
KDM5 biology to combat cancer and disease? Histone deacetylase
inhibitors have long been the “king” of the epigenetic pharmaceutical
industry, with drugs such as Valproic acid, Entinostat and Romadepsin
showing large potential in the clinic and earning FDA approval (Song et al,
2011). However, little has been done targeting demethylase enzymes as
possible treatment options. Recent studies have demonstrated the release
of therapeutic agents against KDM1 and studies of agents against JMJD2
demethylases (Hamada et al, 2010), and novel assays are being developed
to screen and identify novel candidates against these targets (Yu et al,
2012). The KDM5 family is not special in this contextual activity. The
importance of context and the flexibility that KDMs in general bring to
transcriptional control is the key to a variety of processes. Understanding
how and when the KDMs interact with both each other and the basal
transcriptional machinery will likely provide clues into a myriad of
diseases.
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