Deubiquitinating enzymes as novel anticancer targets
Benjamin Nicholson1, Jeffrey G Marblestone, Tauseef R Butt
1Progenra, Inc., 271A Great Valley Parkway, Malvern, PA 19355, USA. nicholson@progenra.com
Abstract:
Tagging proteins with mono- or poly-ubiquitin is now recognized as a multifaceted and universal means of regulating cell growth and physiology. It does so by controlling the cellular lifetime of nearly all eukaryotic proteins and the cellular localization of many critical proteins. Enzymes of the ubiquitin pathway add (ligases) or remove (deubiquitinases [DUBs]) ubiquitin tags to or from their target proteins in a selective fashion. Similarly to the kinases and their corresponding phosphatases, ubiquitin ligases and DUBs have become actively studied molecular oncology targets for drug discovery. Approximately 79 functional DUBs exist in the human proteome, suggesting that selective intervention is a reasonable therapeutic objective, with the goal of downregulating or ablating oncogene products or, alternatively, upregulating or sparing tumor suppressors. In the following review, this fascinating class of regulatory enzymes will be described, and specific examples of DUBs that are viable targets for anticancer therapy will be considered.
Insights
Deubiquitinases (DUBs) regulate protein lifespan and localization, impacting cell growth. Targeting these enzymes offers a promising strategy for developing novel anticancer therapies by modulating oncogenes and tumor suppressors.
Area of Science:
- Biochemistry and Molecular Biology
- Cellular Regulation
- Oncology
Background:
- Protein ubiquitination is a key regulatory mechanism controlling protein stability and localization in eukaryotic cells.
- Deubiquitinases (DUBs) are enzymes that remove ubiquitin tags, counterbalancing the action of ubiquitin ligases.
- Dysregulation of the ubiquitin-proteasome system is implicated in various cancers.
Purpose of the Study:
- To review the multifaceted roles of deubiquitinases (DUBs) in cellular physiology.
- To explore the therapeutic potential of targeting DUBs in cancer treatment.
- To identify specific DUBs as viable targets for anticancer drug discovery.
Main Methods:
- Review of existing literature on ubiquitin pathway enzymes and their roles in cell regulation.
- Analysis of the human proteome to identify functional deubiquitinases (DUBs).
- Consideration of DUBs as molecular oncology targets for drug development.
Main Results:
- There are approximately 79 functional deubiquitinases (DUBs) in the human proteome.
- DUBs play critical roles in regulating protein turnover and localization, influencing cell growth and physiology.
- Selective targeting of DUBs presents a viable therapeutic strategy in oncology.
Conclusions:
- Deubiquitinases (DUBs) are essential regulators of cellular processes and are implicated in cancer.
- Targeting specific DUBs can modulate oncogene activity or stabilize tumor suppressors.
- DUBs represent a promising class of enzymes for the development of novel anticancer therapeutics.
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