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.

Fig. 1. The PTEN continuum in tumor suppression.

PTEN function can be compromised via genetic disruption, which results in a stepwise loss of PTEN (50% or 100%). Posttranslational modifications, including ubiquitination and deubiquitination, of PTEN can fine-tune PTEN functionality via a continuum of tumor suppression. Notably the phenotypes acquired throughout the continuum of functional PTEN loss are differentially manifested depending on tissue type.

Fig. 2. Schematic diagram of the domain architecture of DUBs.

Two classes of proteases (cysteine proteases and metalloproteases) are DUBs, with most DUBs cysteine proteases. Cysteine protease DUBs can be classified into six subfamilies based on their DUB domains: USP, UCH, OTU, MJD, MINDY, and ZUFSP. Metalloprotease DUBs include a JAMM DUB domain. USP, ubiquitin-specific protease; UCH, ubiquitin C-terminal hydrolase; OTU, ovarian tumor protease; MJD, Machado–Joseph disease protease; MINDY, motif interacting with Ub-containing novel DUB family; ZUFSP, zinc finger with UFM1-specific peptidase domain; JAMM, JAB1/MPN/Mov34 metalloenzyme.

Fig. 3. Proposed model showing the mechanisms of DUB action for PTEN.

While HAUSP/USP7 induces deubiquitination and subsequent nuclear exclusion of monoubiquitinated PTEN in the nucleus, where it can control the cell cycle and genomic stability, PML-RARα, NPMc+, and BCR-ABL promote HAUSP-mediated PTEN deubiquitination in blood-borne cancers. USP11 plays a role in the maintenance of the effective levels of both nuclear and cytosolic PTEN for tumor suppression, and interestingly, its expression and activity are regulated by the PTEN/PI3K pathway. Furthermore, in the cytoplasm, USP11, USP13, and (acetylated) OTUD3 catalyze the removal of the K48-linked polyubiquitin chain on PTEN to enhance protein stability, whereas USP10 recognizes and removes the K63-linked polyubiquitin chain from PTEN, leading to PTEN recruitment to the plasma membrane. Ataxin-3 represses PTEN by inhibiting its transcription. PTEN phosphatase and tensin homolog deleted on chromosome 10, HAUSP herpesvirus-associated ubiquitin-specific protease, USP10 ubiquitin-specific protease 10, USP11 ubiquitin-specific protease 11, USP13 ubiquitin-specific protease 13, OTUD3 OTU deubiquitinase 3, PI3K phosphoinositide 3-kinase, PIP2 phosphoinositide-4,5-biphosphate, PIP3 phosphoinositide-3,4,5-triphosphate, mTOR mammalian target of rapamycin, PML promyelocytic leukemia, NPMc+ cytoplasmic nucleophosmin, TRIP13 thyroid hormone receptor-interacting protein 13.