title: 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, 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.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. dchlin11@gmail.com yin_dong@yahoo.com.
authors: De-Chen
authors: DC
authors: Lin
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Liang
authors: L
authors: Xu
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Ye
authors: Y
authors: Chen
authors: 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.
authors: Haiyan
authors: H
authors: Yan
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Masaharu
authors: M
authors: Hazawa
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California.
authors: Ngan
authors: N
authors: Doan
authors: Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California.
authors: Jonathan W
authors: JW
authors: Said
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Ling-Wen
authors: LW
authors: Ding
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Li-Zhen
authors: LZ
authors: Liu
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Henry
authors: H
authors: Yang
authors: 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.
authors: Shizhu
authors: S
authors: Yu
authors: 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.
authors: Michael
authors: M
authors: Kahn
authors: 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. dchlin11@gmail.com yin_dong@yahoo.com.
authors: Dong
authors: D
authors: Yin
authors: 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.
authors: H Phillip
authors: HP
authors: Koeffler
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein