Ubiquitin levels: the next target against gynecological cancers?

Abstract

Ubiquitylation is a tightly regulated process that is essential for appropriate cell survival and function, and the ubiquitin pathway has shown promise as a therapeutic target for several forms of cancer. In this issue of the JCI, Kedves and colleagues report the identification of a subset of gynecological cancers with repressed expression of the polyubiquitin gene UBB, which renders these cancer cells sensitive to further decreases in ubiquitin production by inhibition of the polyubiquitin gene UBC. Moreover, inducible depletion of UBC in mice harboring tumors with low UBB levels dramatically decreased tumor burden and prolonged survival. Together, the results of this study indicate that there is a synthetic lethal relationship between UBB and UBC that has potential to be exploited as a therapeutic strategy to fight these devastating cancers.

Figure 1. Further depletion of ubiquitin levels in cancer cells with low levels of UBB expression results in synthetic lethality.

Cancer cells with repressed expression of the UBB polyubiquitin gene (UBB^LO) likely have lower cellular ubiquitin levels and, therefore, are sensitive to further depletion of ubiquitin by inhibition of the polyubiquitin gene UBC. In contrast, cells with normal ubiquitin levels (UBB^WT) remain viable after depletion of UBC. Alternatively, proteasome and DUB inhibitors could constitute effective treatment options for cancers with reduced ubiquitin, as these inhibitors also lower ubiquitin levels.