ABSTRACT
Cancer is a leading cause of death in humans, with a complex and dynamic nature that makes it challenging to fully comprehend and treat. The Mammalian Sterile 20-Like Kinase 4 (MST4 or STK26) is a serine/threonine-protein kinase that plays a crucial role in cell migration and polarity in both normal and tumor cells via activation of intracellular signaling molecules and pathways. MST4 is involved in tumor cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), survival, and cancer metastasis through modulation of downstream signaling pathways including the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways. Additionally, MST4 interacts with programmed cell death 10 (PDCD10) to promote tumor proliferation and migration. MST4 phosphorylates autophagy related 4B cysteine peptidase (ATG4B) to mediate autophagy signaling, promote tumor cell survival and proliferation, and contribute to treatment resistance. Taken together, MST4 functions as an oncogene and is a promising therapeutic target which deserves further exploration.
Subject(s)
Protein Serine-Threonine Kinases , Signal Transduction , Animals , Humans , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Extracellular Signal-Regulated MAP Kinases/metabolism , Mammals/metabolism , Oncogenes , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
The mammalian STE 20-like protein kinase 4 (MST4) gene is highly expressed in several cancer types, but little is known about the role of MST4 in breast cancer, and the function of MST4 during epithelial-mesenchymal transition (EMT) has not been fully elucidated. Here we report that overexpression of MST4 in breast cancer results in enhanced cell growth, migration, and invasion, whereas inhibition of MST4 expression significantly attenuates these properties. Further study shows that MST4 promotes EMT by activating Akt and its downstream signaling molecules such as E-cadherin/N-cadherin, Snail, and Slug. MST4 also activates AKT and its downstream pro-survival pathway. Furthermore, by analyzing breast cancer patient tissue microarray and silicon datasets, we found that MST4 expression is much higher in breast tumor tissue compared to normal tissue, and significantly correlates with cancer stage, lymph node metastasis and a poor overall survival rate (p < 0.05). Taken together, our findings demonstrate the oncogenic potential of MST4 in breast cancer, highlighting its role in cancer cell proliferation, migration/invasion, survival, and EMT, suggesting a possibility that MST4 may serve as a novel therapeutic target for breast cancer.
