KLF5 Activation Promotes Malignant Transformation to Drive Development of Lung Squamous Cell Carcinoma

Tumorigenesis is a multistep process requiring alterations in various gene expression programs. The transcription factor KLF5 is frequently genomically amplified and activated in multiple epithelial cancers, highlighting the need to define its role in the transformation of normal epithelium to cancer. In this study, we used genetically engineered organoids to identify the function of KLF5 in tumorigenesis of multiple endodermal epithelial cancers. KLF5 activation drove a series of morphologic and molecular events during the stepwise transformation of normal airway epithelium toward lung squamous cell carcinoma (LUSC) by remodeling protein biosynthesis and energy metabolism. Inhibition of ribosome biogenesis and oxidative phosphorylation attenuated the malignant progression of LUSC driven by KLF5. In summary, this study identified KLF5 as a crucial transcriptional modulator in LUSC oncogenesis and indicated that KLF5-activated LUSC may be therapeutically vulnerable to inhibition of ribosome biogenesis and oxidative phosphorylation. SIGNIFICANCE: KLF5 fuels lung squamous cell carcinoma progression by hijacking ribosome synthesis and energy metabolism pathways, pinpointing clinically actionable vulnerabilities that could transform treatment strategies for patients with KLF5-driven tumors.