Ubiquitin based therapy of aggressive cancer cell populations

DESCRIPTION (provided by applicant): The degradation of most cellular proteins is regulated by coordinated addition and removal of ubiquitin by families of ubiquitin E3 ligases and deubiquitylating enzymes (DUBs) respectively. DUBs proteolytically cleave ubiquitin molecules from proteins resulting in modifications of protein activity, localization and function. Several DUBs are aberrantly regulated in cancer, including the best studied, USP7, selective inhibitors of which are active in cancer models. A second DUB, USP22, is another validated anticancer target, being one of 11 genes in the death-from-cancer gene signature, a component of the human SAGA transcriptional cofactor complex regulating myc transcription, and a regulator of the expression of p21, thehistone deacetylase Sirt 1, and p53 activity. USP22 is overexpressed in oral squamous cell carcinoma, breast, non-small cell lung, colorectal, and other cancers and its expression is inversely correlated with survival. Unlike most other DUBs, USP22 e