Krüppel-like factors (KLFs) are a family of DNA-binding transcriptional regulators with diverse and essential functions in a multitude of cellular processes, including proliferation, differentiation, migration, inflammation and pluripotency. In this Review, we discuss the roles and regulation of the 17 known KLFs in various cancer-relevant processes. Importantly, the functions of KLFs are context dependent, with some KLFs having different roles in normal cells and cancer, during cancer development and progression and in different cancer types. We also identify key questions for the field that are likely to lead to important new translational research and discoveries in cancer biology.

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Background & Aims Klf4 (Krüppel-like factor 4; GKLF) is a DNA-binding transcriptional regulator highly expressed in skin and gastrointestinal epithelia, specifically in regions of cellular differentiation. Homozygous null mice for Klf4 die shortly after birth from skin defects, precluding their analysis at later stages. The aim of this study was to analyze the function of Klf4 in keratinocyte biology and epithelial homeostasis in the adult by focusing on the squamous lined esophagus. Methods Using the ED-L2 promoter of Epstein-Barr virus to drive Cre, we obtained tissue specific ablation of Klf4 in the squamous epithelia of the tongue, esophagus, and forestomach. Results Mice with loss of Klf4 in esophageal epithelia survived to adulthood, bypassing the early lethality. Tissue-specific Klf4 knockout mice had increased basal cell proliferation and a delay in cellular maturation; these mice developed epithelial hypertrophy and subsequent dysplasia by 6 months of age. Moreover, loss of Klf4 in vivo was associated with increased expression of the pro-proliferative Klf5, and Klf4 downregulated Klf5 both transcriptionally and post-transcriptionally. Using gene expression profiling, we also showed decreased expression of critical late-stage differentiation factors and identified alterations of several genes important in cellular differentiation. Conclusions Klf4 is essential for squamous epithelial differentiation in vivo and interacts with Klf5 to maintain normal epithelial homeostasis.

Squamous cell cancers account for more than half of all human cancers, and esophageal cancer is the sixth leading cause of cancer death worldwide. The majority of esophageal squamous cell carcinomas have identifiable p53 mutations, yet the same p53 mutations are found at comparable frequencies in pre-cancerous dysplasia, indicating that transformation requires additional somatic changes yet to be defined. Here we show that the zinc finger transcription factor KLF5 transactivates NOTCH1 in the context of p53 mutation or loss. KLF5 loss limited NOTCH1 activity and was sufficient on its own to transform primary human keratinocytes harboring mutant p53, leading to formation of invasive tumors. Restoration of NOTCH1 blocked transformation of KLF5-deficient and p53 mutant keratinocytes. While human dysplastic epithelia accumulated KLF5, KLF5 expression was lost concurrently with NOTCH1 in squamous cell cancers. Taken together, these results define KLF5 loss as a critical event in squamous cell transformation and invasion. Our findings suggest that KLF5 may be a useful diagnostic and therapeutic target in esophageal squamous carcinomas and possibly more generally in other cancers associated with p53 loss-of-function.

Migration of epithelial cells is critical for normal homeostasis in gut and skin, but the factors regulating this process are not completely understood. The zinc finger transcription factor Klf5 (IKLF; BTEB2) is highly expressed in proliferating cells of esophagus, skin, and other organs. We hypothesized that Klf5 regulates keratinocyte migration via the integrin-linked kinase (ILK), which, like Klf5, is localized to basal keratinocytes. We stably transduced mouse primary esophageal keratinocytes to overexpress Klf5 or small interfering RNA against Klf5. Klf5 overexpression in keratinocytes increased migration and correlated directly with ILK expression and activation. ILK expression restored migratory capacity in keratinocytes with suppression of Klf5, whereas ILK small interfering RNA blocked the increased migration resulting from Klf5 overexpression. By chromatin immunoprecipitation, electromobility shift assay, and luciferase reporter assays, we confirmed that ILK was a direct target for Klf5. In addition, Klf5 induced the activation of the ILK targets Cdc42 and myosin light chain, which are critical for cell migration and motility but not Rac1, AKT, or GSK3␤.Overall, these results demonstrate that Klf5 is a key regulator of cell migration via ILK and provide new insight into the regulation of epithelial cell migration.Spatial separation of proliferating and differentiating cells is a common theme throughout the epithelia of the luminal gastrointestinal tract, the skin, and several other organs (1-3). Migration of cells within these epithelia is critical for differentiation and normal homeostasis. A number of different epithelial types are found throughout the human body, of which the stratified squamous epithelium, which lines the esophagus, skin, oral cavity, and several other organs, is the most common. In stratified squamous epithelia, the basal layer is composed of both epithelial stem cells and transit-amplifying cells (4 -6). These transit-amplifying cells are partially committed, rapidly proliferating cells that originate from asymmetric divisions of the stem cells and then migrate, both within the basal layer and from the basal layer, toward the surface (7,8). While migrating within the basal layer, the transit-amplifying cells undergo several rounds of rapid proliferation and clonal expansion. Keratinocytes then undergo additional differentiation during migration through the suprabasal and superficial layers, losing their proliferative capacity.A number of pathways are known to be critical for keratinocyte migration (reviewed in Ref. 9). Interactions of keratinocytes with the extracellular matrix are especially important for migration, and the integrins and the integrin-linked kinase (ILK) 2 play key roles in transducing signals from the extracellular matrix. ILK is an adaptor protein that couples integrins and growth factor receptors to a variety of downstream signaling events, influencing cell adhesion, proliferation, migration, differentiation, and survival (10 -12). ILK binds to the cytoplasmic...