Simple Summary Reversible epithelial to mesenchymal transition (EMT) plays a key role in establishing a malignant phenotype by assuring cancer cell plasticity critical for cancer progression by allowing a small fraction of cancer cells to detach from primary lesions and outgrow at metastatic sites. Cancer cell plasticity is associated with cancer stem cell properties contributing to chemoresistance, metastasis, and poor clinical outcomes. Dysregulated RNA-binding proteins are key players in controlling the RNA metabolism, including mRNA processing, export, and translation, and have been implicated in cancer cell plasticity. In this study, we demonstrated that aberrantly expressed RNA-binding protein La is critical for transforming growth factor beta-induced EMT and for gaining cancer stem cell properties. Understanding the function of aberrant RNA-binding protein expression in cancer cell plasticity reveals prospects for identifying novel therapeutic targets. Background: the aberrant overexpression of predominantly nuclear localizing RNA-binding protein (RBP) La contributes to proliferation, mobility, and chemoresistance of cancer cells and tumor growth in mice. Methods: studies included cancer tissue microarrays (TMAs) analyses, cancer tissue data mining, transforming growth factor beta (TGF beta)-induced cancer cell plasticity studies, three dimensional sphere growth, epithelial to mesenchymal transition (EMT) assays, analysis of cancer stem cell (CSC) marker expression, and post-translational modification of cancer-associated La protein. Results: we demonstrated that significant overexpression of RBP La in lung and head and neck cancer tissue correlates with poor overall survival. Furthermore, small interfering RNA-mediated depletion of La reduced proliferation and migration of cancer cells, blocked TGF beta-induced EMT, and diminished both EMT and CSC marker expression. Rescue experiments with La wildtype but not RNA chaperone domain activity-defective La mutant increased the expression of those cancer progression markers, suggesting a critical role of La's RNA chaperone activity in this process. La depletion in cancer cells also significantly decreased sphere growth in the presence of TGF beta. Interestingly, TGF beta treatment induced phosphorylation of La at threonine 389 (pLa(T389)) only in adherents but not in 3D growing cultures. Conclusion: our study suggests that the TGF beta/AKT/pLa(T389) signaling pathway regulates cancer cell plasticity.