The Dependency Map (DepMap) is a genome-wide pooled
CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many
different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene
knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of
CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell
lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can
include activity in the same or parallel pathways or membership in the same protein complex or the
same pathway.
We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment
analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein
interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The
“Evidence” column contains the PPIDs in which the interaction appears as well as whether there is
support for the association by an INDRA statement. As another approach to identify potential
interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for
proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB;
it has previously been observed that proteins in the same complex are frequently significantly
co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided.
And, we determined whether co-dependent genes yield similar transcriptomic signatures
in the Broad Institute's Connectivity
Map (CMap). A CMap score greater than 90 is considered significantly similar.
Using the biological processes and other Gene Ontology terms from well characterized DUBs as a
positive control, several gene set enrichment analyses were considered. Threshold-less methods
like GSEA had relatively poor results.
Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map
correlations yielded the best results and is reported below.
GO Identifier
GO Name
GO Type
p-value
p-value (adj.)
q-value
Literature Mining
INDRA was used to automatically assemble known mechanisms
related to USP11 from literature and knowledge bases.
The first section shows only DUB activity and the second shows all other results.
Deubiquitinase Activity
psp
cbn
pc
bel_lc
signor
biogrid
lincs_drug
tas
hprd
trrust
ctd
vhn
pe
drugbank
omnipath
conib
crog
dgi
|
rlimsp
isi
tees
geneways
eidos
trips
medscan
sparser
reach
XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In this study, we show that USP11 has no effect on TbetaRI stability in human lung fibroblast cells, though Al-Salihi et al. 21 showed that USP11 de-ubiquitinates TbetaRI.
For example, the closely related DUBs USP4, USP11 and USP15 have been reported to modulate TGFbeta signalling by deubiquitylating the type I TGFbeta receptor ALK5 [XREF_BIBR - XREF_BIBR].
USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20-Cul3 (Cullin 3) and Roc1 complex.
Remarkably, USP11 was able to antagonize RNF4- and Roc1-Cul3-KLHL20-mediated PML ubiquitination in 293T cells and GBM cell line U87 (XREF_SUPPLEMENTARY).
USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20-Cul3 (Cullin 3)-Roc1 complex.
To show that deubiquitination of SPRTN by USP11 is direct, we purified SFB-SPRTN, Myc-USP11, and Myc-USP11 C318S proteins from HEK 293T cells and performed an invitro DUB reaction by incubating SFB-SPRTN alone or with Myc-USP11 or Myc-USP11 C318S purified proteins.
We observed that USP11, but not USP11 C318S catalytic mutant, deubiquitinated SPRTN (XREF_FIG E, anti-Ub blot) and reduced SPRTN auto-cleavage products (XREF_FIG E, IP blot).
Once it is ubiquitinated, IkappaBalpha can be deubiquitinated by its associated USP11 in collaboration with USP15 to prevent excessive NF-kappaB activation induced by TNFalpha.
However, we found that overexpression of USP11 C318A mutant only partially rescued the inhibitory effect of USP11-WT on TNFalpha induced IkappaBalpha ubiquitination (XREF_SUPPLEMENTARY) as well as TNFalpha- and IKKbeta induced NF-kappaB activation (XREF_SUPPLEMENTARY).
These mechanisms might be of therapeutic importance in cancer, because defective HR renders cells susceptible to inhibition of base excision repair (BER) mediated by poly (ADP-ribose) polymerase 1 (PARP1) XREF_BIBR - XREF_BIBR : the deubiquitylating enzyme (DUB) ubiquitin carboxyl-terminal hydrolase 11 (USP11) deubiquitylates partner and localizer of BRCA2 (PALB2) during S and G2 phases following DNA damage, allowing the formation of the BRCA1, PALB2, and BRCA2 complex and HR repair to advance in these phases of the cell cycle 64.
Since recombinant USP11 can de-ubiquitylate PALB2 (1-103) in vitro (XREF_FIG), these results suggest that USP11 promotes the assembly of the BRCA1, PALB2, and BRCA2 complex by reversing the inhibitory ubiquitylation on the PALB2 Lys20/25/30 residues.
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability: USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C(MMC) regulates the stability of BRCA2 in a USP11-dependent manner [117].
USP11 was shown to interact with and deubiquitinates BRCA2 and as well counteracts RNF4 induced SUMO-ubiquitin hybrid chains, suggesting the pleiotropic roles at DSBs sites [XREF_BIBR].
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability : USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C (MMC) regulates the stability of BRCA2 in a USP11 dependent manner [XREF_BIBR].
Although when overexpressed USP11 can deubiquitinate BRCA2 in vivo, it does not antagonize the MMC-induced ubiquitination and degradation of BRCA2 [185].
While BRCA2 could be deubiquitinated by USP11 in transient overexpression assays, a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels.
We demonstrate that knockdown of USP11 increases the ubiquitination of TbetaRII, whereas overexpression of USP11 greatly decreases ubiquitination of TbetaRII.
Together, these data suggest that deubiquitination of TGFBR2 by USP11 effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis.
Together, these data suggest that deubiquitination of TGFBR2 by USP11 effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis.
Taken together, USP11 deubiquitinates and stabilizes LPA1, and LPA induced switching LPA1 association with USP11 to Nedd4L plays a critical role in LPA1 ubiquitination and degradation (XREF_FIG e).
The stability of LPA1 is up-regulated by ubiquitin specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1 mediated pro inflammatory effects.
The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects.
The result showed that both USP10 and USP11 specifically co-precipitated with NP-HA (lanes 1, 3 and 4, lower panel), consistent with the published result, and NP could be deubiquitinated by only USP11 but not USP10 (lanes 3 and 4, upper panel).
Endogenous depletion of RanBPM inhibited the stabilizing action of USP11 on Mgl-1, indicating the crucial role of RanBPM in controlling the deubiquitination of Mgl-1 by USP11.
USP11 knockdown in HaCaT cells increased ubiquitination of XPC as compared to control cells, suggesting that USP11 is important in maintaining NER capacity, as USP11 mediates XPC deubiquitination at the chromatin following UVB damage [XREF_BIBR].
As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCF SKP2, CRL4 CDT2, and APC/C CDC20 in a cell-cycle-independent manner.
Nevertheless, MEL18 and BMI were deubiquitylated by USP7 and USP11, two chromatin bound components of polycomb and repressive complex 1 complex components that influence the transcriptional regulation of p16INK4a [XREF_BIBR].
For example, the closely related DUBs USP4, USP11 and USP15 have been reported to modulate TGFbeta signalling by deubiquitylating the type I TGFbeta receptor ALK5 [XREF_BIBR - XREF_BIBR].
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability: USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C(MMC) regulates the stability of BRCA2 in a USP11-dependent manner [117].
Several lines of evidence point towards a critical role for USP11 in regulating BRCA2 stability : USP11 interacts and co-purifies with BRCA2, USP11 deubiquitylates BRCA2, USP11 depletion sensitises cells to DNA damaging agents and finally, mitomycin C (MMC) regulates the stability of BRCA2 in a USP11 dependent manner [XREF_BIBR].
Our results revealed that USP11 promoted EMT in ovarian cancer by deubiquitinating Snail, and USP11 may be a novel therapeutic target for ovarian cancer treatment.
We demonstrate that knockdown of USP11 increases the ubiquitination of TbetaRII, whereas overexpression of USP11 greatly decreases ubiquitination of TbetaRII.
Overexpression of USP11 reduces TbetaRII ubiquitination and increases TbetaRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA.
Although the function of USP11 in DSB repair will be discussed below, recently it is reported that USP11 directly and specifically deubiquitylates gammaH2AX, but not H2A (K119) and H2B (K120) in vitro[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP-11 deubiquitylates specific substrates which play key roles in correct microtubule nucleation (RanBPM) [XREF_BIBR]; antigen presenting cell function (RELB) [XREF_BIBR]; inflammation, immunity, cell proliferation and apoptosis (TNFa induced NK-kB, and IKKa and p53 signaling pathway) [XREF_BIBR, XREF_BIBR]; and E7 modulated cell growth and transformation (HPV-16E7) [XREF_BIBR].
Remarkably, assessing deubiquitination levels of eIF4B in cell based assays we found that USP11 (wt and Asp mutant) was able to deubiquitinate eIF4B compared with GFP transfected cells, which did not occur for USP11 S453A.
Furthermore, knockdown of USP11 expression enhanced TNFalpha mediated IkappaBalpha ubiquitination and NF-kappaB activation but had no effect on TNFalpha mediated MAPK activation.
Collectively, the present findings indicated that USP11 binded to and deubiquitinated NF90, thereby stabilizing the protein expression level and promoting HCC cell proliferation and metastasis.
Remarkably, USP11 was able to antagonize RNF4- and Roc1-Cul3-KLHL20-mediated PML ubiquitination in 293T cells and GBM cell line U87 (XREF_SUPPLEMENTARY).
We observed that USP11, but not USP11 C318S catalytic mutant, deubiquitinated SPRTN (XREF_FIG E, anti-Ub blot) and reduced SPRTN auto-cleavage products (XREF_FIG E, IP blot).
Ubiquitin-specific peptidase 11 ( USP11 ) has been reported to promote transforming growth factor beta ( TGFbeta ) signaling which plays essential role underlying RIPF .
While wild-type (wt) USP11 significantly enhanced TGFbeta induced transcriptional reporter activity, the catalytically inactive mutant USP11 (C318S) had no effect (see XREF_FIG d and the electronic supplementary material, figure S3).
Ubiquitin-specific peptidase 11 (USP11) has been reported to promote transforming growth factor β (TGFβ) signaling which plays essential role underlying RIPF.
USP11 overexpression in T EFF cells enhanced the activation of the TGF-beta pathway and promoted T REG or T H 17, but not Th1, cell differentiation in vitro and in vivo, an effect abrogated by USP11 gene silencing or the inhibition of enzymatic activity.
The DUBs USP4, USP11, USP15, and UCH37 have previously been demonstrated to modulate TGF-beta pathway activity by directly deubiquitinating the TbetaRI, resulting in increased TbetaRI stability (XREF_FIG) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.
11 In congruence with this, our results indicate that USP11 acts as an oncogene, because USP11 overexpression promotes the proliferation of melanoma cells, whereas knockdown of USP11 exhibits the opposite function.
Furthermore, we demonstrate that USP11 mediates the proliferation of melanoma cells via NONO because the effect of USP11 knockdown on melanoma cells could be rescued by introducing NONO.
For example, the aberrant expression of USP11 was found to interact with nuclear factor 90 and promote its deubiquitination, to promote the proliferation and metastasis of hepatocellular carcinoma.
Taken together, these results indicate that the E2F1 and USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.
In congruence with previous report, 11 USP11 knockdown inhibited the proliferation of A375, which could be reversed by the introduction of ectopic NONO.
Functionally, USP11 mediated melanoma cell proliferation via the regulation of NONO levels because ablation of USP11 inhibits the proliferation which could be rescued by ectopic expression of NONO protein.
Namely, USP11 has been shown to promote the proliferation and metastasis of hepatocellular carcinoma (HCC), but the underlying molecular basis is poorly understood.
Our observation that depletion of USP11 or inhibition using a non specific inhibitor such as Mitoxantrone significantly reduces DLBCL proliferation further supports the need for the development of USP11 specific inhibitors for targeting DLBCL.
Functionally, USP11 mediated melanoma cell proliferation via the regulation of NONO levels because ablation of USP11 inhibits the proliferation which could be rescued by ectopic expression of NONO protein.
Physiologically, USP11 depletion suppresses cell proliferation and wound healing in lung epithelial cells, and these effects are reversed by E2F1 and PEG10 overexpression.
A series of in vitro and in vivo experiments revealed that USP11 promoted autophagy through AMPK/Akt/mTOR pathway via stabilizing valosin containing protein (VCP).
The above experimental results have confirmed that USP11 could not only mediate the resistance to 5-Fu, but also induce autophagy in colorectal cancer cells.
USP11 promotes autophagy through AMPK / Akt / mTOR signaling pathway in a VCP-dependent manner Our previous experiments have confirmed that USP11 can promote autophagy in colorectal cancer cells , however , the underlying mechanisms were still unknown .
Taken together these data, we hypothesized that USP11 might mediate resistance to 5-Fu by inducing autophagy in colorectal cancer cells and verified the hypothesis in follow-up experiments.
Our study investigated the role of ubiquitin specific protease 11 (USP11) in CRC chemotherapy and found that USP11 could induce resistance to 5-fluorouracil by activating autophagy.
In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.
Here, we show that the deubiquitinase USP11 restricts autophagy and that knockout (KO) of USP11 in mammalian cells results in elevated autophagic flux.
We also demonstrate that depletion of the USP11 homolog H34C03.2 in Caenorhabditis elegans triggers hyperactivation of autophagy and protects the animals against human β-amyloid peptide 42 aggregation-induced paralysis.
Taken together, these results indicate that the E2F1 and USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.
Importantly, Hey1 induced repression of USP11 was abrogated partially by mutating either of the first two Sp1 sites and completely by disrupting both (XREF_FIG), suggesting that Hey1 acts through Sp1 binding sites to repress USP11.
Using luciferase reporter assay, we found that Hey1 repressed the USP11 promoter activity and that the +171/+335 (0.16 K) region of USP11 promoter was responsible for this repression (XREF_FIG).
Thus, Hey1 functions as a transcriptional corepressor in USP11 transcription regulation and a complex crosstalk among transcriptional factors, histone modifiers and DNA methylation is involved in Hey1 mediated repression of USP11.
In the reciprocal experiments, Hey1 knockdown in U87 and U251 cells upregulated USP11 mRNA, USP11 protein and PML protein, but not PML mRNA (XREF_FIG).
Consistent with the regulation of PML protein stability by USP11, Hey1 induced USP11 downregulation resulted in a concomitant reduction of PML protein but not mRNA.
However, it was recently demonstrated that Notch and Hey1 transcriptionally represses the expression of the PML deubiquitinase USP11, thereby down-regulating PML protein levels.
Three examples of deubiquitinating enzymes for TbetaR-I are ubiquitin specific peptidase-4 (USP4), -11 (USP11) and -15 (USP15), all of which antagonize the effect of SMAD7 and strongly induce TGF-beta1 signalling [XREF_BIBR].
As USP11 promotes TGFbeta-1 signaling through stabilization of TbetaRII, we hypothesize that USP11 may have a critical role in the development of lung fibrosis.
We verified that USP11 deficiency remarkably reinforced tight junction in the endothelial cells and alleviated TGF-beta1 to inhibit fibrosis of fibroblast cells .
Here we report that a deubiquitinating enzyme, USP11, promotes LPA1 stability by reduction of LPA1 ubiquitination, resulting in enhanced LPA-LPA1 signal pathway.
Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS induced inflammatory responses and lung injury in preclinical murine models.
In summary, our study identifies the functions of Usp11 mediated Sox11 stabilization in cortical development, provides an explanation for the association of Usp11 mutation with neurological disorder, and highlights the importance of deubiquitination triggered protein stabilization in the developmental process.
Knockdown of Usp11 in N2a cells using three independent short hairpin mediated RNAs (shRNAs) markedly reduced Sox11 protein level without affecting its mRNA level (XREF_FIG and fig.
For example, the aberrant expression of USP11 was found to interact with nuclear factor 90 and promote its deubiquitination, to promote the proliferation and metastasis of hepatocellular carcinoma.
USP11 promoted tumor growth and metastasis in CRC via the ERK and MAPK pathway by stabilizing PPP1CA, suggesting USP11 is a potential prognostic marker.
Namely, USP11 has been shown to promote the proliferation and metastasis of hepatocellular carcinoma (HCC), but the underlying molecular basis is poorly understood.
Overall, we suggest that USP11 promotes HCC cell metastasis, and we provide the first evidence of the prognostic significance of USP11 expression in HCC, which suggests that USP11 is a promising therapeutic target for the treatment of HCC.
Taken together, these results indicate that the E2F1 and USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.
Burkhart et al., using a fluorescent based high-throughput assay, screened more than 2000 FDA approved chemical entities and reported that mitoxantrone inhibits USP11 activity under in-vitro conditions.
Our observation that depletion of USP11 or inhibition of USP11 by a non-specific USP11 inhibitor Mitoxantrone significantly sensitized triple negative breast cancer cells to the chemo-drug cisplatin further supports USP11 as a potential target for anti-cancer treatment.
Indeed, depletion of USP11 or inhibition of USP11 by a non-specific inhibitor Mitoxantrone led to significantly sensitization of triple negative breast cancer cells to the chemo-therapeutic agent cisplatin further confirming the therapeutic value of targeting USP11.
87,107,108 Mitoxantrone, a PARPi that targets the USP11 key enzyme that interacts with BRCA2, has been shown to be 40- to 20,000-fold more potent than the current gemcitabine first-line treatment in 2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Interestingly, knockdown of both USP15 and USP11 expression leads to an increased basal protein level of IkappaBalpha, suggesting that USP11 and USP15 cooperatively modulate IkappaBalpha turnover.
USP11 is able to modulate TNF-alpha-induced NF-kappaB activation through regulation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) stability.
Neither USP11 overexpression nor depletion in SK-Mel-28 and A375 cells had significant influence on NONO mRNA levels, indicating that USP11 positively regulates NONO at the protein levels, but not at the transcriptional levels.
As anticipated, overexpression of USP11 could up-regulate NONO in the absence of MG132, whereas MG132 pretreatment effectively eliminated USP11 mediated change of NONO levels.
In line with this notion, we showed that mouse Usp11 was repressed by the Notch and Hes1 axis, as overexpression of an active form of Notch (Notch intracellular domain, referred to as NIC) or Hes1 in a neuroblastoma cell line N2a diminished Usp11 expression and the promoter activity of Usp11 gene.
However, it was recently demonstrated that Notch and Hey1 transcriptionally represses the expression of the PML deubiquitinase USP11, thereby down-regulating PML protein levels.
Since our previous study found that human USP11 transcription is repressed by the Notch pathway, the up-regulation of Usp11 is likely a consequence of Notch inactivation upon the induction of neuronal differentiation.
In line with this notion, we showed that mouse Usp11 was repressed by the Notch and Hes1 axis, as overexpression of an active form of Notch (Notch intracellular domain, referred to as NIC) or Hes1 in a neuroblastoma cell line N2a diminished Usp11 expression and the promoter activity of Usp11 gene.
Accordingly, overexpression of constitutively active Notch (Notch intracellular domain, referred as NIC) in U87 and U251 cells downregulated USP11 and PML expression (XREF_FIG).
NF-kappaB signaling is negatively regulated by USP11 or USP15 mediated removal of K48 linked ubiquitin chains from IkappaBalpha [XREF_BIBR, XREF_BIBR].
USP11 is able to modulate TNF-alpha-induced NF-kappaB activation through regulation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) stability.
However, down-regulation of USP11 dramatically enhances NF-kappaB activity in response to tumor necrosis factor-alpha, indicating that IKKalpha does not require activation of NF-kappaB.
However, we found that overexpression of USP11 C318A mutant only partially rescued the inhibitory effect of USP11-WT on TNFalpha induced IkappaBalpha ubiquitination (XREF_SUPPLEMENTARY) as well as TNFalpha- and IKKbeta induced NF-kappaB activation (XREF_SUPPLEMENTARY).
As expected, the depletion of USP11 decreased Mgl-1 expression and increased ubiquitination level of Mgl-1, but the mRNA level of Mgl-1 was decreased by the depletion of USP11.
As expected, the depletion of USP11 decreased Mgl-1 expression and increased ubiquitination level of Mgl-1, but the mRNA level of Mgl-1 was decreased by the depletion of USP11.
The results showed that USP11 overexpression significantly enhanced the resistance of HCT8 cells to 5-Fu compared with the control group, whereas the opposite effect was observed in USP11 knockdown HCT116 cells (P < 0.05, Student 's t test).
The above experimental results have confirmed that USP11 could not only mediate the resistance to 5-Fu, but also induce autophagy in colorectal cancer cells.
The experimental results showed that USP11 overexpression could enhance CRC cells resistance to 5-Fu, and knockdown of USP11 could result in CRC cells being more vulnerable to 5-Fu.
Taken together these data, we hypothesized that USP11 might mediate resistance to 5-Fu by inducing autophagy in colorectal cancer cells and verified the hypothesis in follow-up experiments.
Inhibition of USP11 expression reduces p53 levels and IKKalpha expression , as well as increasing the response of the NF-kappaB pathway to TNFalpha ( 197 ) .
Further, rescue experiments were conducted invivo to validate the function of the USP11/p53/KLF2/NF-kappaB axis in ICH induced inflammation, which confirmed that USP11 silencing blocked the release of pro inflammatory cytokines following ICH by downregulating p53, thus protecting against neurological impairment.
Recent studies have demonstrated the pivotal roles of ubiquitination in PML stability mediated by an E3 ligase UHRF1 or deubiquitinase USP11 in cancers XREF_BIBR, XREF_BIBR.
While USP40 shRNAs did not affect PML expression (XREF_SUPPLEMENTARY), knockdown of USP11 by three independent shRNAs induced downregulation of PML protein but not PML messenger RNA (XREF_FIG).
This overexpression of USP11 increased PML levels (XREF_FIG) and decreased several GBM malignant traits, such as cell proliferation, migration and invasion (XREF_FIG).
In the reciprocal experiment, USP11 depletion in a low-grade glioma cell line H4 not only reduced PML levels but also promoted cell proliferation, migration and invasion (XREF_FIG).
We also provide mechanistic insights into KLF4 degradation and show that USP11 depletion inhibits growth and chemoresistance of HCC cells by enhancing KLF4 stability.
To investigate whether down-regulation of USP11 exhibits protective effects against LPS induced lung injury, USP11 levels in the mouse lungs were down-regulated by usp11 shRNA in a lentiviral vector delivery system (XREF_FIG d).
As shown in XREF_FIG B & C, while elevated expression of wild-type USP11 led to transformation of MCF10A and increased acini overgrowth, the expression of mutant USP11 without catalytic activity (Cys318 is replaced by Ala) failed to promote colony formation as well as acini overgrowth.
In this study, we found that the autophagy of colorectal cancer cells with overexpression of USP11 was significantly enhanced after treated with 5-Fu, while the autophagy of colorectal cancer cells with knockdown of USP11 was significantly weakened after treated with 5-Fu.
After 48 hours of treatment with different concentrations of 5-Fu, we found that 5-Fu dramatically upregulated USP11 expression in a dose dependent manner in HCT8 cells.
In this study, we found that the autophagy of colorectal cancer cells with overexpression of USP11 was significantly enhanced after treated with 5-Fu, while the autophagy of colorectal cancer cells with knockdown of USP11 was significantly weakened after treated with 5-Fu.
Indeed, USP11 was noted to be phosphorylated by S6Kinase that increases its interaction with eIF4B and subsequently enhanced cancer promoting gene translation.
When cellular USP11 was knocked down, the amounts of vRNA and cRNA of the wild-type virus increased by about 2.5-fold ( Figure 7A, lane 1 versus lanes 2 and 3) , indicating that USP11 inhibits viral RNA replication as previously mentioned; with the mutant virus defective in NP ubiquitination (K184R), however, there was no significant difference in viral RNA synthesis between USP11 knockdown and control cells ( Figure 7A, lanes 4-6) .
This result further supports the conclusion that USP11 inhibits viral RNA replication through deubiquitinating NP.Ubiquitination is a posttranslational modification, in which ubiquitin chains or single ubiquitin molecules are linked to target proteins, giving rise to poly-or monoubiquitination (Weissman, 2001) .
f, i The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells performed and showed that USP11 expression was downregulated at the mRNA and protein levels in U87, U251 and N9 cells upon the activation of EGFR-vIII (Fig. 5c, d) .
f, i The knockout of both HDAC1 and HDAC2 upregulated USP11 at the mRNA and protein levels in U87-vIII, U251-vIII and N9-vIII cells performed and showed that USP11 expression was downregulated at the mRNA and protein levels in U87, U251 and N9 cells upon the activation of EGFR-vIII (Fig. 5c, d) .
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K and AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11.
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K/AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11 (Fig. 5e, h).
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K and AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11.
LY294002 was used to treat U87-vIII, U251-vIII and N9-vIII cells, and PI3K/AKT pathway inhibition resulted in the transcriptional and translational upregulation of USP11 (Fig. 5e, h).
Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis.
Interestingly , upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux , a potential mechanism through which USP11 may enhance ferroptosis .
Deng and his colleagues found that the deubiquitinase USP11 could inhibit cell cycle progression from G1 to S phase though stabilizing P21 [XREF_BIBR].
The highest affinity USP11 peptide binder fused to a cellular delivery sequence induced significant nuclear localization and cell cycle arrest in S phase, affecting the viability of different mammalian cell lines.
Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins.
Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins [XREF_BIBR].
Importantly, knockdown of either USP7 or USP11 reduces the total and chromatin bound pool of BMI1 and MEL18, and the effects can be mitigated by inhibiting proteasome function.
Regulation of the stability of the PRC1 complex also appears to be another facet, as the de-ubiquitination of the PRC1 components BMI1 and MEL18 by the ubiquitin-specific proteases 7 and 11 has been shown to increase their abundance (Maertens et al., 2010), whereas the loss of these ubiquitin-specific proteases promotes INK4A transcriptional activation.