Latest @ CSI

Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma (Cancer Res, May 2015)

Lin DC1*, Xu L2*, Chen Y2, Yan H3, Hazawa M2, Doan N4, Said JW4, Ding LW2, Liu LZ2, Yang H2, Yu S5, Kahn M6, Yin D7, Koeffler HP8.

* Co-first author
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore
3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
4 Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California.
5 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China. Key Laboratory of Neurotrauma, Variation and Regeneration of Education Ministry and Tianjin Municipality, Tianjin, China.
6 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. Department of Molecular Pharmacology and Toxicology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
7 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
8 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. National University Cancer Institute, National University Health System and National University of Singapore, Singapore, Singapore. Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California.\

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, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating 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.

From Dechen_Fig

Figure: Model of PARK2 functions in glioma.

References

Lin DC1, Xu L2, Chen Y2, Yan H3, Hazawa M2, Doan N4, Said JW4, Ding LW2, Liu LZ2, Yang H2, Yu S5, Kahn M6, Yin D7, Koeffler HP8. Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma. Cancer Res. 2015 May 1;75(9):1815-27. PMID: 25877876. [PubMed] [Read by QxMD]