DEUBIQUITINATING ENZYMES PROMOTE CANCER PROGRESSION AND METASTASIS VIA REGULATING PROTEIN STABILITY
Author ORCID Identifier
Date of Graduation
Genes and Development
Doctor of Philosophy (PhD)
Jeffrey M. Rosen
Sendurai A. Mani
Deubiquitinating enzymes (DUBs, also called deubiquitinases) are enzymes that remove monoubiquitin or polyubiquitin chains from target proteins. DUBs have critical roles in cell homeostasis and signal transduction, as they regulate protein degradation, subcellular localization, and protein-protein interaction. Deregulation of DUBs contributes substantially to tumor formation and progression, and therefore targeting DUBs may be a promising cancer therapy strategy. My dissertation focuses on identifying the DUBs of EZH2 and SNAI1, two proteins critical for cancer progression and metastasis, and establishing these DUBs as promising anti-cancer targets.
EZH2, the catalytic component of the PRC2 complex, silences gene transcription by histone methylation. High levels of EZH2 are a marker of advanced breast cancer and correlate with poor clinical outcomes in many cancers. Although EZH2 enzymatic inhibitors have shown antitumor effects in EZH2-mutated lymphoma and ARID1A-mutated ovarian cancer, many cancers do not respond, because EZH2 can promote cancer independently of its histone methyltransferase activity. Here we identified ZRANB1 (also called Trabid) as an EZH2 deubiquitinase. ZRANB1 binds, deubiquitinates, and stabilizes EZH2. Depletion of ZRANB1 in breast cancer cells results in EZH2 destabilization and growth inhibition. Systemic delivery of ZRANB1 siRNA leads to marked antitumor and antimetastatic effects in preclinical models of triple-negative breast cancer (TNBC). A small-molecule inhibitor of ZRANB1 destabilizes EZH2 and inhibits the viability of TNBC cells. In breast cancer patients, ZRANB1 levels correlate with EZH2 levels and survival outcomes. These findings suggest the therapeutic potential for targeting the EZH2 deubiquitinase ZRANB1.
SNAI1 (also known as Snail or SNAIL1), a major transcription factor inducing the epithelial-mesenchymal transition (EMT), promotes tumor metastasis and induces resistance to apoptosis and chemotherapy. Here we identified USP37 as a SNAI1 deubiquitinase. USP37 binds, deubiquitinates, and stabilizes SNAI1. Overexpression of the wild-type USP37, but not its catalytically inactive mutant C350S, promotes cancer cell migration. Depletion of USP37 inhibits cancer cell migration, which can be reversed by SNAI1 overexpression. Taken together, USP37 is a SNAI1 deubiquitinase and a potential therapeutic target to inhibit tumor metastasis.
In summary, our studies identified the EZH2 deubiquitinase ZRANB1 and the SNAI1 deubiquitinase USP37 as two promising targets to prevent tumor progression and metastasis.
deubiquitinase, EZH2, ZRANB1, breast cancer, SNAI1, USP37, EMT, ubiquitination, degradation