USP22 Regulates Oncogenic Signaling Pathways to Drive Lethal Cancer Progression

Abstract

Increasing evidence links deregulation of the USP22 deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well-defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor (AR) accumulation and signaling, and that it enhances expression of critical target genes co-regulated by AR and MYC. USP22 not only reprogrammed AR function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression whcih drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.

Histone H2B monoubiquitination: roles to play in human malignancy

“…Polycomb/BMI1-driven pathways are active in both normal stem cells and some highly malignant cancers. Recent expansion of this study has confirmed that USP22 is a critical enzyme associated with end-stage disease and that its levels are especially elevated in drug-resistant tumours (Schrecengost et al 2014).…”

ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth

“…Because USP22 is overexpressed in several highly aggressive cancers (Glinsky, 2006; Ji et al, 2015; Schrecengost et al, 2014), we next asked if depletion of USP27X impacts tumor formation and progression in a mouse xenograft model. USP27X depleted or control MB-MDA-231 cells were injected subcutaneously into immune-compromised mice (Figure 7E, F).…”

SIRT1 Activation by a c-MYC Oncogenic Network Promotes the Maintenance and Drug Resistance of Human FLT3-ITD Acute Myeloid Leukemia Stem Cells

“…USP22 is part of a death-from-cancer gene signature (Zhang et al, 2008) associated with poor prognosis in a variety of cancers (Schrecengost et al, 2014). To date, it is known to be part of the SAGA complex required for c-MYC-related transformation (Zhang et al, 2008).…”