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

Abstract

Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.

E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis

“…The molecular mechanism by which PARK2 exerts its tumor suppressive function in melanoma is, in part, through the induction of cellular apoptosis, as revealed by the strong upregulation of the anti-apoptotic factors BCL-2 and BCL-XL in PARK2-silenced melanoma cells and their downregulation upon PARK2 overexpression in vitro and in vivo. Our findings are consistent with a recent report showing that PARK2 directly binds to and ubiquitinates BCL-XL (40) and other members of the BCL-2 family, such as MCL1 (41). There is evidence in other cancer types that PARK2 targets both Cyclin D1 and E1 for degradation (42), and it interacts with both β-catenin and EGFR to promote their ubiquitination in glioblastoma (9).…”

PARK2 inhibits osteosarcoma cell growth through the JAK2/STAT3/VEGF signaling pathway

“…PARK2 deficiency also resulted in the suppression of caspase activation and rendered hepatocytes resistant to apoptosis 21 . Recently, Gong et al reported that PARK2 directly binds and ubiquitinates BCL-XL, which regulates mitochondrial outer membrane permeability and apoptosis 39 . In the present study, the Hoechst staining assay and flow cytometry assay showed that additional apoptotic cells were induced in PARK2 overexpression cells.…”

Biological and Clinical Implications of Comorbidities in Parkinson’s Disease

“…For example, dysregulation of PARK1 and PARK4 , associated with some familial forms of PD, are observed in cancers such as adenocarcinoma, lung, colorectal, brain, melanoma, prostate and non-Hodgkin lymphomas (Fung et al, 2003 ; Matsuo and Kamitani, 2010 ; Bethge et al, 2014 ; Li et al, 2015 ). Similarly, genetic alterations in PARK2 , also linked to familial PD, have been observed in glioblastoma, lung, colorectal, renal cell carcinoma, melanoma and pancreatic cancers (Veeriah et al, 2010 ; Gong et al, 2014 , 2017 ; Hu et al, 2015 ; Inzelberg et al, 2016b ). PINK1 (PARK6) a kinase involved in the regulation of autophagy and the cell cycle, has been involved in glioblastoma, and ovarian cancers (Berthier et al, 2011 ; Devine et al, 2011 ; O’Flanagan et al, 2016 ).…”