Regulation of the Krüppel-like Factor 6 Tumor Suppressor: Ras Promotes Cancer Cell Growth Via Alternative Splicing-mediated Inactivation of Klf6

KLF6 is a ubiquitously expressed Krüppel-like transcription factor whose role in vitro and in vivo role has not been fully identified. Like other members of the Krüppel-like family, KLF6 contains a conserved C-terminal three zinc finger DNA-binding domain (C2H2 motifs) and a unique N-terminal transactivation domain. KLF6 directly binds DNA at GC box promoter elements. Transcriptional targets of KLF6 include collagen 1, transforming growth factor beta 1 (TGF¿1), types I and II TGF¿ receptors, urokinase type plasminogen activator (uPA), and the human immunodeficiency virus long terminal repeat (HIV-1 LTR). Here, we identify a novel mechanism of carcinogenesis, whereby oncogenic Ras signaling enhances alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinomas. These Ras-dependent splice forms are shown to abrogate KLF6-mediated growth suppression, and ectopic KLF6 splice variant expression can restore a Ras-transformed phenotype.