The equilibrium of tumor suppression: DUBs as active regulators of PTEN

Abstract

PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have shown that several deubiquitinating enzymes, including HAUSP/USP7, USP10, USP11, USP13, OTUD3 and Ataxin-3, can remove ubiquitin from ubiquitinated PTEN in cancer-specific contexts and thus reverse ubiquitination-mediated PTEN regulation. Researchers continue to reveal the precise molecular mechanisms by which cancer-specific deubiquitinases of PTEN regulate its roles in the pathobiology of cancer, and new methods of pharmacologically for modulating PTEN deubiquitinases are critical areas of investigation for cancer treatment and prevention. Here, we assess the mechanisms and functions of deubiquitination as a recently appreciated mode of PTEN regulation and review the link between deubiquitinases and PTEN reactivation and its implications for therapeutic strategies. Cancer: Reactivating a tumor suppressor Studying ways to reactivate a tumor-suppressing protein called PTEN may help in finding new cancer therapies. PTEN represses a signaling pathway that, when over-activated, strongly influences cells to become cancerous. Although some cancers are caused by mutations of PTEN itself, new research shows that proteins called deubiquitinases (DUBs), which regulate stability and activity of target proteins, can turn on and off PTEN activity and cancer. Su Jung Song at Soonchunhyang University, Cheonan-si, South Korea, and Min Sup Song at The University of Texas, Houston, USA, and coworkers have reviewed how DUBs can affect PTEN, reporting on the molecular mechanisms of cancer-specific DUBs, and highlighting the potential to pharmacologically target DUBs in order to boost PTEN activity and suppress cancer development. This review illuminates a promising new approach to developing therapies for several types of cancer.