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Introduction
The post-translational modification of proteins by the covalent linkage of ubiquitin targets those proteins for degradation
by the proteasome, and this process involves the participation of both ubiquitinating enzymes and deubiqui-tinating enzymes.
Although deubiquitinating enzymes constitute a large family in the ubiquitin_proteasome system, their biological functions
and pathophysiological roles remain largely unknown and have only just begun to be understood. In recent years, more and
more studies have revealed the involvement of deubiquitinating enzymes in cancers as well as in other diseases. In this
review, we will mainly focus on the emerging roles of this class of enzymes in the development and progression of cancers.
Molecular functions of deubiquitinating enzymes
Ubiquitin-mediated protein degradation and lysosomal protein degradation are the 2 mechanisms for intracellular protein
turnover. The ubiquitin-mediated mechanism is further classified into the ubiquitin/proteasome pathway and
ubiquitin/aggresome pathway. The ubiquitin/proteasome system is the major non-lysosomal proteolytic mechanism in the cytosol and
nucleus of eukaryotic cells, lysosomal, and the
ubiquitin/aggresome pathway. An important function of this
mechanism is the degradation of abnormal proteins generated
under normal and stress conditions. The substrates of this
system include many cystolic, nucleic, and integral
membrane proteins, such as transcription factors, cell cycle
regulators, and signal transducers[1]. The degradation of a
protein via the ubiquitin_proteasome pathway involves 2
successive steps: (1) the conjugation of multiple ubiquitin
moieties to the substrate; and (2) the degradation of the
tagged protein by the 26S proteasome complex.
The enzymatic reactions of the ubiquitin pathway have
mostly been elucidated. In these reactions, proteins are
targeted for degradation by covalent ligation to ubiquitin, a 76
amino acid polypeptide that is universally distributed among
eukaryotes and highly conserved. The ubiquitin_protein
conjugation requires the sequential execution of 3 types of
enzymes (Figure 1). The C-terminal glycine residue of
ubiquitin is activated in an ATP-dependent process by an
ubiquitin-activating enzyme, E1. Activated ubiquitin is then
transmitted to a cysteine residue of an
ubiquitin-conjugating enzyme (ubiquitin carrier protein), E2. In the last step
catalyzed by an ubiquitin-protein ligase (E3), ubiquitin is
linked by its C-terminus in an amide isopeptide linkage to a
e-amino group of the lysine residues of the substrate protein.
This conjugation cascade is highly substrate specific.
The modification of proteins by ubiquitin is reversible.
Ubiquitinated proteins are not only subject to degradation,
but also to deubiquitination. When tagged proteins are
subjected to degradation by the 26S proteasome complex, it
requires the release of free and reusable ubiquitin. The
deubi-quitination reactions, which require accurate proteolytic
processing at the C-terminal glycine of ubiquitin, are catalyzed
by deubiquitinating enzymes (Figure 2). The substrates for
these enzymes include precursor forms of ubiquitin,
conjugates resulting from non-specific side reactions of
E1-S-ubiquitin/E2-S-ubiquitin with cellular nucleophiles,
coval-ently-linked ubiquitin substrates, and poly-ubiquitin chains.
Deubiquitinating enzymes are isopeptidases and consist of
2 classes: ubiquitin C-terminal hydrolases and
ubiquitin-specific processing proteases. Ubiquitin C-terminal hydrolases
are papain-like thiol proteases with a 230 amino acid core
catalytic domain and share significant sequence similarity to
the neuron-specific human protein PGP9.5 (UCH-L1). These
enzymes cleave ubiquitin derivatives with small or
disordered C-terminal domains[2,3]. Most of this class of enzymes
is relatively small with a molecular weight less than 40 kDa.
Ubiquitin C-terminal hydrolases are known to have
important roles in development and neural function. For example,
during the establishment of long-term synaptic facilitation
in Aplysia, the induction of a protein with UCH enzyme
activity was observed[4]. Ubiquitin-specific processing
proteases are a much larger group of thiol proteases and are
very divergent with a molecular weight ranging from 50 to
250 kDa. This class of enzymes is known to be involved in
the regulation of signal transduction, growth, and
development[3]. Both deubiquitinating enzyme classes have a specific,
tight binding site for ubiquitin. Although the exact and
specific physiological roles of deubiquitinating enzymes have
not been fully established, the following functions are
generally accepted: (1) processing of ubiquitin precursors; (2)
recycling of adventitiously trapped catalytic intermediates;
(3) proofreading of protein ubiquitination; (4) recycling of
ubiquitin from polyubiquitinated proteins following
commitment to degradation; (5) keeping proteasomes free of ubiquitin
chains; and (6) maintaining free ubiquitin
concentrations[1]. The functions and molecular basis of deubiquitination and
deubiquitinating enzymes are increasingly being understood
over the past several years. For example, it is now known
that deubiquitination of protein substrates is tightly coupled
with degradation in the proteasome[5,6], and the inactivation
of the deubiquitinating enzyme can completely prevent
protein degradation[5]. However, due to the large number of
members in the deubiquitinating enzyme family, it is not
surprising to see that different members execute totally
different functions. It was found that UBP6, a
proteasome-associated cysteine protease, delays protein
degradation[7]. More interestingly, a recent study demonstrated that ubiquitin
C-terminal hydrolase-L1 possesses ligase activity as well as
hydrolase activity, and these 2 opposing enzymatic
activities affect the degradation of a-synuclein and susceptibility
to Parkinson's disease[8].
Aberrant expression of deubiquitinating enzymes in human cancers
Several types of deubiquitinating enzymes were found
to be upregulated in cancer cells. Ubiquitin C-terminal
hydrolase-L1, identical to the neuron-specific protein gene
product PGP9.5 and widely expressed in neuronal tissues
(1%_2% of brain proteins) at all stages of neuronal differentiation
was originally suggested as a neuroendocrine
marker[9]. Two decades ago there were reports that tumors of
neuroendocrine origin, such as small cell carcinoma, showed positive
staining for PGP9.5[10,11]. Recently, Jen and colleagues
examined the expression of PGP9.5 in normal lung epithelium, lung
tumor cell lines, and 98 resected primary non-small-cell lung
carcinomas and observed that the increased expression of
PGP9.5 was specifically associated with cancer
development[12]. In primary non-small-cell lung carcinomas, 54% (53/98)
of the cases had positive PGP9.5 staining, and this protein
was present in 44% (29/66) of stage I and 75% (24/32) of
stages II and IIIA non-small-cell lung
carcinomas[12]. The high expression of PGP9.5 also occurs in other types of cancer.
The evaluation of the expression of PGP9.5 in 69 resected
ductal carcinomas of the pancreas and in normal pancreatic
tissues revealed a significant negative correlation between
the overexpression of PGP9.5 and postoperative
survival[13]. PGP9.5-negative pancreatic cancer patients had significantly
better survival rates compared with those who were PGP9.5
positive[13]. In colorectal cancer, the same group also
examined the expression of PGP9.5 in primary colorectal cancers
and correlated the results with the pathological
features[14]. In colorectal cancer, 46% (33/74) of the specimens showed
positive staining with PGP9.5 in most tumor cells, whereas
no PGP9.5 expression was detected in adjacent normal
epithelium. A correlation analysis revealed 2 significant
differences in maximal tumor size and the extent of the
tumor[14]. More recently, the overexpression of ubiquitin C-terminal
hydrolase-L1 was reported in human myeloma and
medullary thyroid carcinoma cells[15]. These studies indicate that
the expression of PGP9.5 is closely associated with cancer
progression, and suggest that this protein could be a useful
a tumor marker for diagnosis and prognosis. In our studies
on the multidrug resistance phenotype, we found that
ubiquitin C-terminal hydrolase-L1 is overexpressed in
several drug-resistant cancer cell lines. However, the exact role
of ubiquitin C-terminal hydrolase-L1 (PGP9.5) and its
regulation in cancer remains unknown. Al-Katib
et al demonstrated that ubiquitin C-terminal hydrolase-L1 expression could be
induced by the phorbol ester,
12-O-tetradecanoylphorbol-13-acetate, and by bryostatin, in acute lymphoblastic
leukemia and suggested a role of this enzyme in B-cell
differentiation[16,17]. PGP9.5 was shown to interact and colocalize with
JAB1, a Jun activation domain-binding protein that can bind
to p27kip1[18]. This interaction and colocalization was
suggested to contribute to the degradation of
p27kip1[18], a cyclin-dependent kinase inhibitor whose loss in epithelial cancers
was significantly correlated with the pathological tumor grade
and with high-grade, poorly-differentiated tumors showing
a significantly lower p27 protein than their
well-differentiated counterparts[19]. The decreased level of
p27kip1 is frequently observed in human cancers, including breast, lung,
prostate, colon, skin, and ovarian
cancers[20_22], and has been found to correlate with cancer development and poor
survival[19]. These observations also provide a clue to the
implication of UCH-L1 in cancer development and
progression. In addition, deubiquitinating enzymes are upregulated in
Burkitt's lymphoma, a highly malignant B cell neoplasma,
and some other types of
malignancies[23,24].
Deubiquitinating enzymes: oncogenes or tumor suppressors?
Alterations in the affluence of important regulatory
proteins are the frequently observed defects in malignant cells.
The gain in the function of oncogenes or loss of tumor
suppressor proteins is the umbilical mechanism by which cells
escape normal control on proliferation. Because of the broad
involvement of the ubiquitin_proteasome proteolysis in the
regulation of protein turnover, this pathway may play a vital
role in cancer development and progression. In fact,
considerable insight into the linkage of the ubiquitin_proteasome
pathway with cancer has been gained in recent years. For
example, the tumor suppressor p53 is tightly regulated by
the ubiquitin_proteasome pathway[25,26]. p53 is an unstable
nuclear protein with a half-life of 30 min in normal cells. After
cellular stress or DNA damage, p53 is stabilized through the
downregulation of its degradation, leading to growth arrest
or apoptosis. The ubiquitination-proteasome pathway has
also been reported to play a critical role in the pathogenesis
of breast cancer by affecting the downregulation of growth
factor receptors, such as EGFR/ErbB-1, Neu/ErbB-2, and
ErbB-3/HER3[ (27, 28)]. Nuclear factor-kappa B
(NF-κB) plays a pivotal role in many aspects of tumor development, progression,
and therapy, and its activation relies primarily on the
ubiqui-tination-mediated degradation of its inhibitor
IκB[29]. The role the deubiquitinating enzymes play in the regulation of
those oncogenes or tumor suppressor genes represents an
emerging and interesting research area, and novel functions
of a variety of deubiquitinating enzymes have begun to be
uncovered. Gu et al discovered that herpesvirus-associated
ubiquitin-specific protease [HAUSP, or ubiquitin-specific
protease (USP)7] possesses ubiquitin hydrolase activity that
can stabilize p53 by deubiquitinating the tumor suppressor,
suggesting a tumor suppressor function of this
deubiqui-tinating enzyme[30]. In contrast, using the genetic disruption
approach, Cummins and Vogelstein demonstrated that
MDM2, rather than p53, is the HAUSP substrate, and the
deubiquitination of MDM2 by HAUSP leads to the
destabilization of p53[31]. Gu et
al later also found that HAUSP can deubiquitinate and stabilize MDM2 in a p53-independet
manner, suggesting that HAUSP plays a dynamic role in the
p53_MDM2 pathway[32]. Therefore, HAUSP may have both
tumor suppressive and oncogenic effects, depending on
different circumstances.
USP2a is a deubiquitinating enzyme that is overexpressed
in prostate cancer and plays an important role in regulating
tumor cell survival. Recently, it was found that this
isopeptidase can deubiquitinate and stabilize fatty acid
synthase, an anti-apoptotic protein whose overexpression
is often observed in progressive human
tumors[33]. Therefore, USP2a may act as an oncogenic protein in tumor formation
or cancer progression. USP11 physically associates with
and deubiquitinates BRCA2, but its pro-survival function to
DNA damage is independent of its effect on the
deubiqui-tination of BRCA2[34]. USP28 has also been found to be
involved in DNA damage response; however, its role is to
promote DNA damage-induced apoptosis through
regulating the pro-apoptotic Chk2_p53_PUMA
pathway[35]. On the other hand, BAP1, a ubiquitin C-terminal hydrolase, shows
growth inhibitory effects on cancer cells, and this tumor
suppressor function depends on its interaction with breast
cancer susceptibility gene product
BRCA1[36]. Although the precise mechanism of this interaction is not clear, the
deubiqui-tinating activity of BAP1 is believed to play a key role.
In a high-throughput RNA interference screen to
identify deubiquitinating enzymes involved in cancer,
Brummelkamp et al found that the cylindromatosis tumor suppressor
(CYLD), which is mutated in familial cylindromatosis, is a
USP[37]. CYLD can bind to NEMO (IKKg), deubiquitinate,
and inactivate TNF-receptor-associated factors, leading to
the inhibition of NF-κB activation. The suppression of CYLD
results in the activation of NF-κB and resistance to apoptosis.
The deubiquitinating activity of CYLD, its interaction with
NEMO, and the inhibitory effect on NF-κB activation, were
also discovered in another 2 independent
studies[38,39]. Therefore, deubiquitinating enzymes can be either tumor
suppressor genes depending on their molecular functions
and their roles in diverse signaling pathways. In addition,
deubiquitinating enzymes have been reported to be involved
in the regulation of cell differentiation, apoptosis, and other
physiological or pathological
processes[40_42] (Table 1). With further investigations on deubiquitinating enzymes, it can
be expected that more insight of the roles and functions of
this class of enzymes will be uncovered.
Deubiquitinating enzymes and other cancer-related problems
Pain occurs in approximately 60%_80% of cancer patients
with terminal disease, particularly in patients with metastatic
cancer. Although pain in cancer patients can be attributed
to many factors, direct tumor involvement is the most
common cause. There is evidence that ubiquitin hydrolases might
contribute to the occurrence of cancer pain. Angioleiomyoma
is a solitary subcutaneous tumor characterized by pain in
about half of patients with this tumor. In angioleiomyoma
patients suffering from pain, small nerve fiber
immunoreactivity for ubiquitin C-terminal hydrolase-L1 was observed
within the capsule (77%) and tumor stroma
(69%)[43]. Similar observations were reported in other tumors, such as
gastrointestinal stromal tumors, fibrosarcoma, and
melanoma[44]. These observations suggest that ubiquitin C-terminal
hydrolase-L1 as a part of peripheral components plays a role,
although as yet unclear yet in cancer-associated pain.
Tumor antigens, which are mostly proteins or peptides
expressed or presented by tumor cells, act as signals for
immune effectors (T cells and antibodies) to differentiate
them from normal tissues. Several deubiquitinating enzymes
have been reported to participate in the immune response to
cancer. For instance, the expression of ubiquitin C-terminal
hydrolase-L1 was found to correlate with T-status in
non-small-cell lung cancer[45]. In a proteomic analysis of sera
from lung cancer patients, ubiquitin C-terminal hydrolase-L1
was identified as a tumor antigen that induces a humoral
immune response[46]. More recently, another ubiquitin
hydrolase, ubiquitin C-terminal hydrolase-L3, was found to
be involved in the humoral immune response in human
colon cancer. Yet the exact roles that these ubiqutin
hydrolases play in immune response remain to be elucidated.
Because of the structural and functional similarity, one might
expect that the involvement of more deubiquitinating
enzymes in the immune response to cancer will be uncovered.
Future perspective
Although deubiquitinating enzymes comprise the
largest known family of enzymes in the ubiquitin system, at
present, little is known about the physiological or
pathological roles of those proteins. While deubiquitinating enzymes
share a common fundamental biochemical function, they
nevertheless serve as controllers of highly diverse cellular
processes. In particular, a large number of ubiquitin ligases
have been identified and their association with diseases,
such as cancer, has begun to be uncovered. For example,
the oncogene MDM2 is known to serve as a ubiquitin ligase
for p53 and promotes its degradation. The drugs targeting
MDM2 have already been developed[47]. With increasing
understanding of the functions and roles of the enzymes
involved in protein ubiquitination and deubiquitination, we
can expect to know more about what these
ubiquitin-specific processing proteases and ubiquitin C-terminal
hydrolases exactly do during cancer development and progression.
This knowledge will certainly provide insight into whether
some of those enzymes can serve as prognostic tumor
markers or therapeutic targets for cancer. Drugs targeting the
ubiquitin_proteasome pathway (such as velcade) have
already been proven to be very effective against some types
of cancers[48_52]. Compounds that inhibit the activity of some
ubiqutin C-terminal hydrolases have also been
reported[53], but their implications in the treatment of cancer or other
diseases remain to be investigated. It is conceivable that drugs
targeting deubiquitinating enzymes will sooner or later be
used in treating cancers and other human diseases.
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