Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma

Abstract

PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, while depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through down-regulating the intracellular level of β-catenin and EGFR. Notably, PARK2 physically interacted with both β-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity dependent manner. Finally, inspired by these newly identified tumor suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt-β-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma.

Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis

“…Cancer-specific mutations have been found in the PARK2 gene [6], [7], [30]. To determine whether these mutations affect the ability of PARK2 to bind BCL-XL, we used site-directed mutagenesis to introduce these mutations into PARK2 cDNA.…”

“…In human malignancies, PARK2 is a tumor suppressor that is mutated and/or deleted, with copy number loss being the dominant mode of alteration [1], [6], [7]. The PARK2 gene encodes a ubiquitin E3 ligase that can target proteins for degradation through the ubiquitin-proteasome system [8], [9].…”

“…The PARK2 gene encodes a ubiquitin E3 ligase that can target proteins for degradation through the ubiquitin-proteasome system [8], [9]. Loss of PARK2 can lead to acceleration of tumorigenesis or enhanced tumor aggressiveness [6], [7], [10], [11].…”

Ubiquitin ligases in oncogenic transformation and cancer therapy

“…In addition to its effects on cyclins, parkin limits AKT activity and WNT–β-catenin signalling (by targeting β-catenin for proteasomal degradation), two major pathways regulating cell growth and survival 85 . Furthermore, PARK2 copy number loss has been implicated in stimulating the PI3K–AKT pathway via mitochondrial dysfunction in PTEN-expressing but not PTEN-null cancers 86 : mechanistically, knockdown of PARK2 in cancer cells impaired mitochondrial metabolism, reflected by decreased ATP levels, increased oxidative stress, activation of AMP-activated protein kinase (AMPK) and phosphorylation and activation of endothelial nitric oxide synthase (eNOS) 86 .…”

PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation

“…Importantly, PARK2 has previously been associated with the activation of the Akt pathway (Fallon et al., 2006, Lin et al., 2015, Yeo et al., 2012); however, the mechanistic evidence behind its functional contribution is unclear. One study showed that Parkin interacts with and ubiquitinates Eps15 to delay the internalization and degradation of its adaptor protein epidermal growth factor receptor (EGFR), thereby promoting PI3K/Akt signaling (Fallon et al., 2006), while a more recent study suggests that Parkin directly interacts with and promotes the ubiquitination of EGFR, leading to diminished activation of EGF-induced PI3K/Akt signaling (Lin et al., 2015). These data highlight the need for further investigation of the molecular events underlying the role of PARK2 depletion in PI3K/Akt-mediated cellular survival.…”