Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma

• Published in: Scientific reports 2016-02, Vol.6 (1), p.21596-21596, Article 21596
• Main Authors: Hwang, Su Jin, Lee, Hye Won, Kim, Hye Ree, Lee, Hong, Shin, Chang Hoon, Yun, Sun-Il, Lee, Dong Heon, Kim, Duk-Hwan, Kim, Kyeong Kyu, Joo, Kyeung Min, Kim, Hyeon Ho
• Format: Article
• Language: English
• Subjects: 42/109; 42/89; 631/67/1612; 631/67/322; Adenocarcinoma - physiopathology; Adenocarcinoma of Lung; Animals; beta Catenin - metabolism; Brain Neoplasms - secondary; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Gene Knockdown Techniques; Humanities and Social Sciences; Humans; Lung Neoplasms - physiopathology; Mice; multidisciplinary; Neoplasm Metastasis - physiopathology; Science; Science (multidisciplinary); Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin-Specific Proteases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21596

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.