p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-08, Vol.79 (16), p.4135-4148
• Main Authors: Ryu, Ki-Jun, Park, Sun-Mi, Park, Seung-Ho, Kim, In-Kyu, Han, Hyeontak, Kim, Hyo-Jin, Kim, Seon-Hee, Hong, Keun-Seok, Kim, Hyemin, Kim, Minju, Yoon, Sung-Jin, Asaithambi, Killivalavan, Lee, Kon Ho, Park, Jae-Yong, Hah, Young-Sool, Cho, Hee Jun, Yook, Jong In, Yang, Jung Wook, Ko, Gyung-Hyuck, Lee, Gyemin, Kang, Yang Jae, Hwangbo, Cheol, Kim, Kwang Dong, Park, Young-Jun, Yoo, Jiyun
• Format: Article
• Language: English
• Subjects: Animals; beta-Transducin Repeat-Containing Proteins - metabolism; Cell Line, Tumor; Dyrk Kinases; Epithelial-Mesenchymal Transition; Female; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Mice, Inbred BALB C; Molecular Docking Simulation; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - metabolism; Serine - metabolism; Snail Family Transcription Factors - chemistry; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Ubiquitination; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-19-0049

Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. SIGNIFICANCE: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.