LIX1L promotes EMT and EGFR-TKIs resistance via nucleolin-mediated ribosomal RNA synthesis in NSCLC.

Limb expression 1-like protein (LIX1L) might be an RNA binding protein involved in post-transcriptional regulation. However, little is known regarding the biological function and mechanism of LIX1L in cancer cells. Here we demonstrate a clear correlation between LIX1L expression and EMT markers in 81 NSCLC tissues and TCGA database, suggesting that LIX1L is a mesenchymal marker. Besides, LIX1L expression is obviously elevated in TGFβ1-induced EMT NSCLC cells, and enhances cell migration, invasion, anoikis resistance, EGFR-TKIs resistance and proliferation. Interestingly, the increased LIX1L expression prominently localizes to the nucleoli, where it physically interacts with the key ribosome biogenesis regulator NCL protein, inducing rRNA synthesis in EMT NSCLC cells. NCL knockdown or inhibition of rRNA synthesis reverses the enhanced EMT functions and proliferation ability caused by LIX1L overexpression in NSCLC cells, indicating that NCL expression and rRNA synthesis participates in LIX1L-mediated biological functions during EMT. Collectively, our findings suggest that the LIX1L-NCL-rRNA synthesis axis is a novel EMT-activated mechanism. Targeting the pathway might be a therapeutic option for EMT and EGFR-TKIs resistance in NSCLC.