Targeting deubiquitinating enzymes in cancer stem cells
Lei et al. Cancer Cell Int
Targeting deubiquitinating enzymes in cancer stem cells
Hu Lei 0
Huizhuang Shan 0
Yingli Wu 0
0 Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/ Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China
Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of stemness-related proteins are essential for CSC maintenance and differentiation, even leading to execute various stem cell fate choices. Deubiquitinating enzymes (DUBs), specifically disassembling ubiquitin chains, are important to maintain the balance between ubiquitination and deubiquitination. In this review, we have focused on the DUBs regulation of stem cell fate determination. For example, we discuss deubiquitinase inhibition may lead stem cell transcription factors and CSCs-related protein degradation. Also, CSCs microenvironment is regulated by DUBs activity. Our review provides a new insight into DUBs activity by emphasizing their cellular role in regulating stem cell fate and illustrates the opportunities for the application of DUBs inhibitors in the CSC-targeted therapy.
Cancer stem cells; Deubiquitinating enzymes; Cancer therapies; CSCs
The existence of cancer stem cells (CSCs) are
considered to play a pivotal role in tumor recurrence,
resistance and progression [
]. There are three main aspects
to effect CSCs maintenance and differentiation,
including transcription factor network, CSC-related proteins
and microenvironment [
]. Conventional cancer
therapy can’t kill cancer stem cells, which will cause cancer
relapse and drug resistance under certain conditions
Ubiquitination is a post-translational modification
process that participates in the covalent conjugation of
small, highly conserved 76 amino acid protein ubiquitin
with the lysine residues of the substrate protein through
the cascade of enzyme reactions, including
E1-activating enzymes, E2-conjugating enzymes, and E3 ligases,
resulting in protein final degradation, relocalization or
activity change. On the contrary, DUB-mediated
deubiquitination removes the ubiquitin labels to protect
substrate proteins from above-mentioned changes caused
by ubiquitination. It has been reported that the
ubiquitination and deubiquitination of the key proteins in stem
cells may determine the fate of cells (Fig. 2). Recently,
DUBs have been demonstrated as promising targets
for cancer therapy [
], their functions in cancer cell
stemness remains elusive. For example, USP54 is
overexpressed in colorectal cancer stem cells and promotes
intestinal tumorigenesis [
]. USP28 confers stem-cell-like
traits to breast cancer cells [
Finding deubiquitinates of transcription factors and
key protein can provide better understand of the
activation mechanism on CSCs, and further deubiquitination
inhibitors can be used to eliminate CSCs in cancer
DUBs and CSC‑associated transcription factors
Embryonic stem cells (ESCs) self-renewal and
differentiation are known to be regulated by a network of
transcription factors including Oct3/4, Sox2, c-Myc, Klf4 and
]. Cancer stem cells share significant
similarity with normal stem cells in biological characteristics
such as quiescence, self-renewal and differentiation [
Sox2 also regulates the differentiation and stemness in
cancer stem cells [
]. USP22 is located directly on the
Sox2 promoter and negatively regulates Sox2
transcription in ESCs [
]. In brain tumor cells, Usp9x was
associated with Sox2 and played key roles in the growth of
tumor cells, but the relationship between them was not
]. Sox2 also regulated DUBs activity by binding
to the promoter region at the transcriptional level, such
as USP7, USP25, USP37, and USP44 [
c-Myc is a classical CSC-related marker, which can be
stabilized by many DUBs. USP37 directly deubiquitinates
and stabilizes c-Myc in lung cancer [
positively regulates c-Myc stability and tumorigenic activity
in mammalian and breast cancer cells [
]. In a subset
of human breast and lung cancers, USP36 interacts with
and deubiquitinates c-Myc [
]. USP28 is required for
c-Myc stability in human tumor cells, which binds to
c-Myc through an interaction with FBW7alpha, an F-box
protein that is part of an SCF-type ubiquitin ligase [
Nanog and ID proteins
Recent studies demonstrated that USP21 maintained the
stemness of mouse embryonic stem cells via stabilization
of Nanog by removing K48-linked ubiquitin chains [
Inhibitor of DNA binding (ID) proteins are transcriptional
regulators that control the timing of cell fate
determination and differentiation in stem and progenitor cells during
normal development and adult life [
]. The small
molecule inhibitor of USP1 promotes ID1 degradation and has
cytotoxicity to leukemic cells [
]. USP1 deubiquitinated
and stabilized ID1, ID2, and ID3 proteins to preserve a
mesenchymal stem cell program in osteosarcoma [
Some pluripotent factors such as Oct3/4, Klf4 and
Lin28 have not been found their DUBs, but all of them
are affected by the 26S proteasome, suggesting a
potential role of DUB for their stabilization in CSCs.
DUBs and CSC‑related proteins
Some CSC-related proteins also control the fate of CSC,
such as SIRT1, P53, PTEN, LSD1, PRC and so on. SIRT1,
a NAD+-dependent histone deacetylase, influences stem
cell aging by controlling mitochondrial biogenesis and
turnover which may be required for self-renewal [
SIRT1 inhibition represents a potential approach to
target leukemia stem cells [
]. USP22 interacts with and
stabilizes SIRT1 by removing polyubiquitin chains
conjugated onto SIRT1 in mouse embryonic development .
P53, tumor suppresser, demonstrates a role for p53
deficiency in enhancing the formation of tumors arising
from stem cells (embryonal carcinoma cells) [
is reported that USP10 deubiquitinates p53, reversing
Mdm2-induced p53 nuclear export and degradation .
Ataxin-3, the machado–joseph disease deubiquitinase,
interacts with p53 and functions as a novel p53 DUB [
USP7 deubiquitinates both p53 and MDM2, one of the
ubiquitin ligases that ubiquitylates p53, thereby
stabilizing both proteins [
]. OTUD1, OTUD5 and USP11
directly deubiquitinating p53 and functional proteins
were required for p53 stabilization [
PTEN loss leads to the development of cancer stem cells,
with the capacity of self-renewal and multi-lineage
]. ATXN3 acts primarily by
repressing PTEN transcription, without altering PTEN protein
stability . However, USP18 overexpression could
stabilize PTEN protein, and USP18 repression decreases
mainly cytoplasmic PTEN [
]. PTEN subcellular
compartmentalization can be regulated by USP7 [
The dysfunction of polycomb repressive complex (PRC)
is closely related to cancer stemness [
represses transcription is only in part dependent on its
ubiquitination activity, and Fbxl10 is reported to recruit
PRC1 to CpG islands and regulate H2A
]. Polycomb gene silencing may require H2A
ubiquitination by PRC1 and H2A deubiquitination by
Polycomb repressive deubiquitinase (PR-DUB). In some
cancer types, PRC1 can be deubiquitinated by USP7,
USP11 and USP26 [
]. PRC2-mediated histone
methylation plays an important role in aberrant cancer
gene silencing and is a potential target for cancer therapy.
The PRC2 proteins EZH2 is frequently overexpressed in
mesothelioma with BAP1 mutation [
deubiquitination enzymes of PRC need to be further explored in
Lysine-specific demethylase 1 (LSD1), the first
identified histone demethylase, maintains cell stemness during
cancer progression [
]. USP7 and USP28 inhibited
LSD1 ubiquitination and stabilized LSD1 protein level
Taken together, CSC-related proteins degradation or
activity inhibition by targeting DUBs is effective for
eliminating cancer stem cells.
DUBs and CSC microenvironment
The microenvironment of CSC has also been reported to
play essential roles in maintenance of cancer stemness.
Tumor specific microenvironments comprise stromal
cells, immune cells, networks of cytokines and growth
factors, hypoxic regions, and the extracellular matrix
(ECM). We summarize the role of CSC
microenvironment from two aspects: hypoxia and inflammation
Hypoxia is considered to be a major feature of the tumor
microenvironment and is a potential contributor to the
CSC phenotype. Hypoxia-inducible factor (HIF)
transcription factors (HIF-1α and HIF-2α) are key mediators
in cancer hypoxia response and help maintain multiple
CSC population [
]. In the presence of oxygen, VHL
tumor suppressor protein interacts with HIF proteins
and this interaction results in the ubiquitination and
degradation of HIF proteins, maintaining low levels of these
transcription factors . However, HIF proteins
stabilization can be regulated by DUBs, such as USP8, USP19
and USP28 [
]. In addition, USP52 is a key
component of P-bodies required to prevent HIF1α mRNA
The inflammatory cytokines modify the cancer
microenvironment, CSCs secretion factors attract the necessary
cells into their areas, enabling them better survive and
escape chemotherapy [
]. Transforming growth factor
β (TGFβ) has the ability to regulate immune cell
populations in inhibiting and promoting tumor formation and
progression active [
]. Cancer cells exposed to IL-6 are
malignant, such as enhanced invasive ability and drug
]. IL-8 promotes angiogenic activity
through the activation of VEGFR2 . USP21 binds to
the promoter region of IL-8 and mediates transcriptional
initiation in stem-cell like property of human renal cell
]. Also, IL-6 and G-CSF levels have been
elevated in lung CSCs [
]. Most inflammatory cytokines
are produced by many kinds of signal pathways and the
deubiquitination of key proteins in the pathway can block
inflammatory cytokines release. For example, TRAF6,
a key regulator in toll-like receptor pathway and NF-κB
pathway, can be regulated by USP4 and A20 [
CSCs are difficult to eliminate by conventional treatment,
mainly due to disorders of signal transduction and
epigenetics. The control of ubiquitination and
deubiquitination of CSC-related proteins determine the difference in
CSCs and the maintenance of pluripotency. DUBs can
protect the stemness of the CSC, thereby maintaining its
activity and further forming a vicious circle. Therefore,
DUBs are very important in the CSC specific treatment.
We summarized the effect of deubiquitinating enzymes
in the regulation of target proteins in Table 1. The
successful inhibition of CSC maintenance and radiation
resistance by USP1 specific inhibitor (pimozide) has been
provided the basis for further clinical trials [
]. It means
that DUB inhibitors may boost more advantages in
CSC-specific therapy than other anti-cancer drugs such
as proteasome inhibitors. For example, b-AP15, a
selective DUB inhibitor, can overcome bortezomib resistance
in multiple myeloma [
]. More relevant basic research
should be carried out to determine the DUBs related to
the CSCs and to identify the mechanisms between them.
Currently commercialized DUB inhibitors are
summarized in Table 2, showing significant pharmacological
effects on cancer cells or cancer stem cells. In general,
strategies involving the use of DUB inhibitors to target
combination therapy of cancer stem cells and
differentiated cancer cells can provide better outcomes for radical
CSCs: cancer stem cells; DUBs: deubiquitinating enzymes; ESCs: embryonic
stem cells; ID: inhibitor of DNA binding; PRC: polycomb repressive complex;
LSD1: lysine-specific demethylase 1; ECM: extracellular matrix; HIF:
hypoxiainducible factor; TGFβ: transforming growth factor β.
HL collected materials and wrote the review. HZS collected materials. YLW
modified and corrected the review. All authors read and approved the final
The authors declare that they have no competing interests.
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National Natural Science Foundation of China (81570118; 81700475).
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