Journal Article

DZNE-2020-01370

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Ubiquitin Carboxyl-Terminal Hydrolases (UCHs): Potential Mediators for Cancer and Neurodegeneration.

Sharma, A. ; Liu, H. ; Tobar-Tosse, F. ; Chand Dakal, T. ; Ludwig, M. ; Holz, F. G. ; Loeffler, K. U. ; Wüllner, U.DZNE* ; Herwig-Carl, M. C. (Corresponding author)

2020
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms21113910

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.

Keyword(s): Brain: metabolism (MeSH) ; Databases, Genetic (MeSH) ; Gene Expression Profiling (MeSH) ; Gene Expression Regulation (MeSH) ; Humans (MeSH) ; Neoplasms: enzymology (MeSH) ; Neurodegenerative Diseases: enzymology (MeSH) ; Phenotype (MeSH) ; Prognosis (MeSH) ; Protein Domains (MeSH) ; Tumor Suppressor Proteins: metabolism (MeSH) ; Ubiquitin Thiolesterase: genetics (MeSH) ; Ubiquitin Thiolesterase: metabolism (MeSH) ; Ubiquitination (MeSH)

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Contributing Institute(s):

1. Biomarkers for Parkinson's disease (AG Wüllner ; AG Wüllner 2)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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