Abstract
The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/β-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24(high) cells to CD44(high) cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression.
Highlights
The ability of epithelial cells to undergo mesenchymal transitions during embryogenesis, wound healing and malignant progression is widely accepted as a core biological process [1, 2]
We surveyed a cDNA library consisting of 651 cDNA clones for 500 human kinases, and identified 55 kinases that activated VimPro better than PIK3CA, a known Epithelial– mesenchymal transition (EMT) promoter [15], with 7 fold induction of vimentin promoter activity relative to GFP control (Fig. 1A)
Consistent with results from the luciferase reporter assay in our cDNA screens, several under-studied kinase candidates and positive controls (FYN and MET) dramatically upregulated the expression of mesenchymal markers, including vimentin, fibronectin and N-cadherin in human mammary gland epithelial cells (HMLE) cells (Fig. 1B)
Summary
The ability of epithelial cells to undergo mesenchymal transitions during embryogenesis, wound healing and malignant progression is widely accepted as a core biological process [1, 2]. Much of the work on EMT regulation is on a few upstream molecules (such as Wnt, Notch, Hedgehog, TGF-β and their receptors), several transcription factors (such as Twist, Snail, Slug, Zeb, SIP1, FoxC2 and Six1) and microRNAs (such as microRNA-200 family members) [1,2,3,4,5,6]. Our knowledge in this critical process is still quite limited, especially in intracellular signaling pathways. Many of these known EMT regulators are traditionally considered as non-druggable or difficult to target
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