Ubiquitin Carboxyl-Terminal Hydrolases (UCHs): Potential Mediators for Cancer and Neurodegeneration

Abstract

Emerging evidence suggests an inverse association between cancer and neurodegenerative diseases (NDD). Although phenotypically different, both diseases display a significant imbalance in the ubiquitination/deubiquitination processes. Therefore, we particularly investigated the expression of ubiquitin C-terminal hydrolases (UCHs: UCH-L1, UCH-L3, UCH-L5 and BAP1), a subfamily of deubiquitinating enzymes (DUBs), using publically available datasets (GTEx, TCGA) and observed altered expression of UCH-L1, UCH-L3, UCH-L5 in 17 cancer types. Interestingly, UCH-L1 (known to be enriched in neurons and interacting with the Parkinson’s disease-associated protein α-synuclein) appeared to be a prognostic indicator of unfavorable outcome in endometrial and urothelial cancer, while increased expression of UCH-L3 and UCH-L5 was associated with poor survival in liver and thyroid cancer, respectively. In normal tissues, UCH-L1 was found to be strongly expressed in the cerebral cortex and hypothalamus, while UCH-L3 expression was somewhat higher in the testis. The occurrence of mutation rates in UCHs also suggests that BAP1 and UCH-L5 may play a more dominant role in cancers than UCH-L1 and UCH-L3. We also characterized the functional context and configuration of the repeat elements in the promoter of DUBs genes and found that UCHs are highly discriminatory for catabolic function and are mainly enriched with LINE/CR1 repeats. Regarding the thesis of an inverse association between cancer and NDD, we observed that among all DUBs, UCHs are the one most involved in both entities. Considering a putative therapeutic potential based on presumed common mechanisms, it will be useful to determine whether other DUBs can compensate for the loss of UCH activity under physiological conditions. However, experimental evidence is required to substantiate this argument.

Advances in deubiquitinating enzymes in lung adenocarcinoma

“…However, the most relevant research on DUBs is in the field of cancer 33 , 34 , including lung, liver 35 , breast 36 , stomach 37 , colon 38 , prostate 39 and ovarian cancers 40 . In this area, the mechanisms of DUBs in different tumors are described, and their potential as cancer therapeutics has attracted attention.…”

Regulator of G Protein Signaling 20 Correlates with Long Intergenic Non-Coding RNA (lincRNAs) Harboring Oncogenic Potential and Is Markedly Upregulated in Hepatocellular Carcinoma

“…There has been a constant search for identifying HCC-related biomarkers, however, most of them showed association with poor prognosis, either in early or advanced HCC [ 4 ]. Notably, two members of the ubiquitin C-terminal hydrolases (UCHs) family, BRCA1-associated protein-1 (BAP1) [ 5 ] and UCH-L3 [ 6 ] have been implicated in the survival rate of this particular cancer. More recently, authors established immuno-autophagy-related long non-coding RNA (IARlncRNA) signature with a prognostic ability in HCC [ 7 ].…”

Comprehensive Profiling of Blood Coagulation and Fibrinolysis Marker Reveals Elevated Plasmin-Antiplasmin Complexes in Parkinson’s Disease

“…No clear modifier or biochemical markers of progression have been identified, with the exception of a progressive decrease in dopaminergic cell function. A number of epidemiological studies have indicated an inverse association between the risk of developing malignancies and PD (except melanoma) [ 4 , 5 ].…”