KLF4 Suppresses Tumor Growth and Metastasis
KLF4, Krüppel-like factor 4, a zinc finger-type transcription factor, is decreased or lost in most gastrointestinal cancers. By transcriptionally regulating its downstream target genes, KLF4 plays important roles of gastrointestinal carcinogenesis, proliferation and differentiation. We have identified KLF4 as suppressor gene in stomach cancer (Wei et al., Cancer Research, 2005; Li et al., Gastroenterology, 2011), pancreatic cancer (Wei et al., Gastroenterology, 2010) and liver cancer (Li et al., Gastroenterology, 2012). We have found that major mechanisms responsible for the loss of KLF4 expression in gastrointestinal cancers are epigenetic alterations, i.e., KLF4 promoter hypermethylation and imbalanced expression of wild-type KLF4 and KLF4α (alternative splicing variant, Wei et al., Gastroenterology, 2010) proteins and that reduced or lost KLF4 expression predicts poor prognosis in PDA. We have systematically compared and contrasted the impacts of KLF4 and KLF4α on the malignant phenotype of human pancreatic cancer. We found KLF4α acts as an oncogene and antagonizes the function of KLF4. KLF4 represses the expression of Sp1 gene and its downstream targets including VEGF, Lamin B1, and FOXM1 at the transcriptional level, while KLF4α does the opposite (Wei et al., Gastroenterology, 2010).
FOXM1 Promotes Oncogenesis and Tumor Progression
FOXM1, also known as MPP2, HNF-3, HFH-11, Win and Trident, is a transcription factor in the FOX superfamily which is characterized by a conserved winged helix DNA-binding domain. FOXM1 is a key regulator of cell cycle and essentially regulates multiple aspects of tumor cell biology. Overexpression of FOXM1 occurs frequently in a wide variety of human tumors and contributes to human cancer pathogenesis, including that of gastrointestinal cancers. Recent studies also suggested that it plays critical roles in pancreatic cancer growth, angiogenesis, invasion and metastasis. Recently, we found that FOXM1 directly bound to β-catenin and is a key component in mediating β-catenin nuclear accumulation and downstream target genes expression. However, the molecular mechanisms underlying FOXM1 dysregulation and its impact on gastrointestinal cancers pathogenesis remain unclear.