Epigenetic regulators such as the polycomb proteins control critical biological functions in both normal stem cells and aggressive human cancer cell types. A gene signature that includes polycomb genes and additional genes co-regulated with polycomb genes was recently identified. The expression of this signature identifies tumors with the cancer stem cell phenotypes of aggressive growth, metastasis and therapy resistance. Most members of this 11- gene signature encode proteins with well-defined roles in human cancer. However the function of the signature member USP22 remained unknown. We recently reported that USP22 is a previously uncharacterized subunit of the human SAGA transcriptional cofactor complex. Within hSAGA, USP22 deubiquitylates histone H2A and H2B, thereby playing a central role in transcription. Furthermore, USP22 is recruited to specific genes by activators such as the MYC oncoprotein, where it is required for transcription. In support of a functional role within the polycomb/cancer stem cell signature, I have recently shown by genetic depletion that USP22 is required for protecting human cancer cells from death induced by genotoxic stress. In this proposal, I will define the precise biochemical events that USP22 overexpression triggers in aggressive human cancer cells in order to protect them from gentoxic stress and death. Ultimately, I will extend my findings from genetic depletion studies to assess whether pharmacological inhibition of USP22 can also be exploited to selectively induce apoptosis in transformed human cells.

Public Health Relevance

USP22 is a previously uncharacterized enzyme that is overexpressed as part of a death-from- cancer gene signature. We have shown that USP22 is a critical regulator of transcription which is important for protecting cancer cells from genotoxic stress and cell death. Here I will extend my initial observations to define how USP22 protect cancer cells from death and assess whether inhibiting USP22 can be exploited to selectively kill aggressive cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA165475-02
Application #
8540100
Study Section
Special Emphasis Panel (ZRG1-F09-A (08))
Program Officer
Schmidt, Michael K
Project Start
2012-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$42,232
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Schrecengost, Randy S; Dean, Jeffry L; Goodwin, Jonathan F et al. (2014) USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Res 74:272-86