Abstract
Ubiquitin-Specific Peptidase 22 (USP22) is a ubiquitin hydrolase, notably catalyzing the removal of the mono-ubiquitin moiety from histone H2B (H2Bub1). Frequent overexpression of USP22 has been observed in various cancer types and is associated with poor patient prognosis. Multiple mechanisms have been identified to explain how USP22 overexpression contributes to cancer progression, and thus, USP22 has been proposed as a novel drug target in cancer. However, gene re-sequencing data from numerous cancer types show that USP22 expression is frequently diminished, suggesting it may also harbor tumor suppressor-like properties. This review will examine the current state of knowledge on USP22 expression in cancers, describe its impact on H2Bub1 abundance and present the mechanisms through which altered USP22 expression may contribute to oncogenesis, including an emerging role for USP22 in the maintenance of genome stability in cancer. Clarifying the impact aberrant USP22 expression and abnormal H2Bub1 levels have in oncogenesis is critical before precision medicine therapies can be developed that either directly target USP22 overexpression or exploit the loss of USP22 expression in cancer cells.
Highlights
Histones are small nuclear proteins (11–15 kDa) and key effectors of DNA compaction
While it is clear that Ubiquitin-Specific Peptidase 22 (USP22) is overexpressed in various cancer types and may promote oncogenesis by altering gene expression, cell death and cell cycle progression, emerging evidence suggests that USP22 harbors tumor suppressor-like properties
By impacting H2Bub1 levels, USP22 partakes in multiple pathways required for the maintenance of genome stability, and USP22 expression may be required to prevent aberrant events underlying genome instability
Summary
Histones are small nuclear proteins (11–15 kDa) and key effectors of DNA compaction. Histones share a common structure comprised of a central globular domain along with carboxy- and amino-terminal tails. The globular domains and the histone tails, which extend from the nucleosome, are the substrates for a vast array of Post-Translational Modifications (PTMs), including acetylation, phosphorylation, methylation and ubiquitination [2]. These PTMs can be viewed as modulating the balance between accessibility and compaction of the chromatin fiber, which regulates essential processes such as transcription, DNA damage repair, chromosome compaction and segregation [2]. USP22 expression is types, more its frequently downregulated in many cancer suggesting target it mayinalso harbor tumor-suppressor properties. USP22 and its impact on H2Bub is essential for the development of precision medicine therapies tailored to the specific genetic context of patients with altered USP22 expression
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