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MSK1 promotes colorectal cancer metastasis by increasing Snail protein stability through USP5-mediated Snail
Keun-Seok Hong1,2, Ki-Jun Ryu3, Hyemin Kim2,4
1Department of Bio and Medical Bigdata (Brain Korea 21 Four), Gyeongsang National University, Jinju, Republic of Korea.
Abstract:
Mitogen- and stress-activated protein kinase 1 (MSK1), a Ser/Thr kinase, phosphorylates nuclear proteins to increase their stability and DNA-binding affinity. Despite the role of MSK1 in promoting cancer progression in colorectal cancer (CRC), the precise molecular mechanisms remain unelucidated. Here we show that MSK1 expression induces the epithelial-mesenchymal transition (EMT) process and increases CRC cell metastasis. Furthermore, we discovered that MSK1 interacts with Snail, a key EMT regulator, and increases its stability by inhibiting ubiquitin-mediated proteasomal degradation. Importantly, MSK1 increased Snail protein stability by promoting deubiquitination rather than inhibiting its ubiquitination. Finally, we identified USP5 as an essential deubiquitinase that binds to Snail protein phosphorylated by MSK1. Based on the experimental data, in CRC, MSK1-Snail-USP5 axis can promote EMT and metastasis of CRC. Together, our findings provide potential biomarkers and novel therapeutic targets for further research in CRC.
Insights
Mitogen- and stress-activated protein kinase 1 (MSK1) promotes colorectal cancer (CRC) metastasis by stabilizing Snail, a key regulator of epithelial-mesenchymal transition (EMT). This involves MSK1-mediated phosphorylation and USP5-driven deubiquitination of Snail.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Mitogen- and stress-activated protein kinase 1 (MSK1) is a Ser/Thr kinase involved in nuclear protein regulation.
- MSK1 is implicated in colorectal cancer (CRC) progression, but its specific molecular roles are not fully understood.
- The epithelial-mesenchymal transition (EMT) is a critical process in cancer metastasis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which MSK1 promotes colorectal cancer (CRC) progression and metastasis.
- To investigate the interaction between MSK1 and Snail, a key regulator of EMT.
- To identify potential therapeutic targets for CRC treatment.
Main Methods:
- Investigated MSK1 expression and its effect on EMT and metastasis in CRC cells.
- Performed co-immunoprecipitation assays to study the interaction between MSK1 and Snail.
- Utilized ubiquitination and deubiquitination assays to analyze Snail protein stability.
- Identified USP5 as a deubiquitinase interacting with MSK1-phosphorylated Snail.
Main Results:
- MSK1 expression induced EMT and increased metastasis in CRC cells.
- MSK1 directly interacts with Snail and enhances its stability by promoting deubiquitination.
- USP5 was identified as a deubiquitinase that binds to phosphorylated Snail, increasing its stability.
- The MSK1-Snail-USP5 axis was shown to promote EMT and metastasis in CRC.
Conclusions:
- MSK1 plays a crucial role in promoting CRC metastasis through the regulation of Snail stability.
- The MSK1-Snail-USP5 signaling axis represents a novel pathway driving EMT and metastasis in CRC.
- These findings suggest MSK1, Snail, and USP5 as potential biomarkers and therapeutic targets for CRC.
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Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...