title: Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma.
abstract: Brain metastasis is the most common type of intracranial cancer and is the main cause of cancer-associated mortality. Brain metastasis mainly originates from lung cancer. Using a previously established in vitro brain metastatic model, we found that brain metastatic PC14PE6/LvBr4 cells exhibited higher expression of β-catenin and increased migratory activity than parental PC14PE6 cells. Knockdown of β-catenin dramatically suppressed the motility and invasiveness of PC14PE6/LvBr4 cells, indicating β-catenin is involved in controlling metastatic potential. Since β-catenin protein was increased without a significant change in its mRNA levels, the mechanism underlying increased β-catenin stability was investigated. We found that ubiquitin-specific protease 4 (USP4), recently identified as a β-catenin-specific deubiquitinylating enzyme, was highly expressed in PC14PE6/LvBr4 cells and involved in the increased stability of β-catenin protein. Similar to β-catenin knockdown, USP4-silenced PC14PE6/LvBr4 cells showed decreased migratory and invasive abilities. Moreover, knockdown of both USP4 and β-catenin inhibited clonogenicity and induced mesenchymal-epithelial transition by downregulating ZEB1 in PC14PE6/LvBr4 cells. Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival. Taken together, our results indicate that USP4 is a promising therapeutic target for brain metastasis in patients with lung adenocarcinoma.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Hye Ree
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Hong
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Shin
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Sun-Il
authors.initials: SI
authors.lastname: Yun
authors.affiliation: Department of Neurosurgery, Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dong Heon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.|Center for Genome Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Duk-Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Kyeong Kyu
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C486203:USP4 protein, human; D051176:beta Catenin; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases