In this issue of Blood, Bedekovics et al have demonstrated that a multifunctional molecule of the ubiquitin system ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced in diffuse large B-cell lymphomas (DLBCLs), and that levels of this molecule are higher in germinal center (GC) B-cell DLBCL (GCB-DLBCL) compared with activated B-cell DLBCL (ABC-DLBCL) and predict poor outcomes.1 

Although the mechanism of induction of UCH-L1 and its physiological functions are meager, the authors provide evidence supporting the hypothesis that UCH-L1 alters gene expression and antigen-specific immunity specifically in GCB cells, at least partially through synergism with the known oncogene in neoplastic germinal centers, BCL6. Previously, the same investigators demonstrated that UCH-L1 is a potent oncogene in vivo showing that its overexpression strongly accelerated lymphomagenesis in transgenic mice.2 

Accumulating data in recent years (although somewhat controversial) suggest that UCH-L1 plays distinct roles in oncogenesis in humans, and that de novo expression of this molecule has been detected in many primary and metastatic cancers as well as transformed cells of different origins.3  Interestingly, the levels of UCH-L1 protein in transformed B lymphocytes are notably higher compared with transformed fibroblasts or epithelial cells.4  In addition, UCH-L1 is likely the most active deubiquitinating enzyme in lymphoid cell lines,5  which suggests that the UCH-L1 deubiquitinase is a significant factor for lymphomagenesis.

Information about transcriptional regulation of the UCH-L1 gene in transformed cells is very limited, although it is likely linked to the tissue of origin. Transcription factors associated with tumorigenesis such as TCF4, PU.1, and nuclear factor–κB (NF-κB)4,6,7  can induce UCH-L1 expression in different cell types in culture including lymphoid. Although UCH-L1 is expressed in both non-GC and GCB cells, Bedekovics et al have observed higher levels in GCB-DLBCL.1  This finding raises an interesting question about which mechanisms drive enhanced induction of the UCH-L1 gene in this subgroup of DLBCL. For example, in the ABC group of DLBCL, which is more often Epstein-Barr virus (EBV) positive, indirect induction of the UCH-L1 gene might be explained by EBV-mediated activation of transcription factors such as NF-κB and PU.1.

Putative direct targets of UCH-L1 deubiquitinating activity remain obscure, and whether UCH-L1 can remove ubiquitin from large molecules such as proteins under physiological conditions is still uncertain, although some direct or indirect targets such as β-catenin and HIF1α have been suggested.6,8 

Although information on biological roles for UCH-L1 in different types of cancer is also far from complete, one such function is emerging. UCH-L1 participates in invasion and metastasis of aggressive carcinoma3,9  and likely activates antiapoptotic signaling during lymphomagenesis.2 

In their study, Bedekovics et al propose a possible explanation of the molecular mechanisms involved in the pathogenesis of GCB-DLBCL: based on their experimental results, the authors conclude that UCH-L1 expression is specifically induced in GCB cells, and that its expression reflects GC identity in B lymphoma. A potential link between UCH-L1 and the BCL6 oncogene is especially interesting because the authors show a substantially higher incidence of lymphoma in BCL6/UCH-L1 double-mutant mice, more than would be expected by additive effects alone.1  In previous work, these investigators demonstrated that UCH-L1 regulates the mammalian target of rapamycin–AKT signaling network in a GCB-DLBCL cell line,2  although it is likely that UCH-L1 is only 1 element by which AKT activity is modulated in DLBCL in vivo. However, the higher levels of UCH-L1 in GCB-DLBCL compared with ABC-DLBCL1  might indicate additional roles for this multifunctional protein in the group of B lymphomas of this origin.

Considering that depletion of UCH-L1 affects expression of multiple genes in transformed B cells,1,10  UCH-L1 is likely to participate in a number of cellular physiological activities in B lymphomas. At this point, the principal findings of the study are evident and significant because there are few clinical biomarkers that are sufficiently robust to offer risk stratification of patients with DLBCL, in particular for those with GCB disease. The data in this study provide an important insight that will assist in identification of patients with GCB disease at high risk for relapse. However, although biomarkers can be useful clinically without an understanding of the underlying biology, further exploration of the functional role of UCH-L1 in the pathogenesis of DLBCL is needed.

Recently, an inhibitor of UCH-L1 deubiquitinase activity, LDN-57444, was used successfully to show that UCH-L1 is a prometastatic molecule in a murine model of pulmonary metastasis.8  This is the first indication that blockage of UCH-L1 might be beneficial for anticancer treatment in vivo. The results of Bedekovics et al pave the way for further studies on the physiological roles of UCH-L1 to be carried out to clarify whether this deubiquitinating enzyme is a therapeutic target in aggressive B-cell lymphomas.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

REFERENCES

REFERENCES
1
Bedekovics
 
T
Hussain
 
S
Feldman
 
AL
Galardy
 
PJ
UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma.
Blood
2016
, vol. 
127
 
12
(pg. 
1564
-
1574
)
2
Hussain
 
S
Foreman
 
O
Perkins
 
SL
, et al. 
The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling.
Leukemia
2010
, vol. 
24
 
9
(pg. 
1641
-
1655
)
3
Suong
 
DN
Thao
 
DT
Masamitsu
 
Y
Thuoc
 
TL
Ubiquitin carboxyl hydrolase L1 significance for human diseases.
Protein Pept Lett
2014
, vol. 
21
 
7
(pg. 
624
-
630
)
4
Bheda
 
A
Yue
 
W
Gullapalli
 
A
Shackelford
 
J
Pagano
 
JS
PU.1-dependent regulation of UCH L1 expression in B-lymphoma cells.
Leuk Lymphoma
2011
, vol. 
52
 
7
(pg. 
1336
-
1347
)
5
Ovaa
 
H
Kessler
 
BM
Rolén
 
U
Galardy
 
PJ
Ploegh
 
HL
Masucci
 
MG
Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells.
Proc Natl Acad Sci USA
2004
, vol. 
101
 
8
(pg. 
2253
-
2258
)
6
Bheda
 
A
Yue
 
W
Gullapalli
 
A
, et al. 
Positive reciprocal regulation of ubiquitin C-terminal hydrolase L1 and beta-catenin/TCF signaling.
PLoS One
2009
, vol. 
4
 
6
pg. 
e5955
 
7
Zhang
 
H
Sun
 
Y
Hu
 
R
, et al. 
The regulation of the UCH-L1 gene by transcription factor NF-κB in podocytes [published correction appears in Cell Signal. 2014;26(2):460].
Cell Signal
2013
, vol. 
25
 
7
(pg. 
1574
-
1585
)
8
Goto
 
Y
Zeng
 
L
Yeom
 
CJ
, et al. 
UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α.
Nat Commun
2015
, vol. 
6
 pg. 
6153
 
9
Hurst-Kennedy
 
J
Chin
 
LS
Li
 
L
Ubiquitin C-terminal hydrolase l1 in tumorigenesis.
Biochem Res Int
2012
, vol. 
2012
 pg. 
123706
 
10
Bheda
 
A
Shackelford
 
J
Pagano
 
JS
Expression and functional studies of ubiquitin C-terminal hydrolase L1 regulated genes.
PLoS One
2009
, vol. 
4
 
8
pg. 
e6764