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.

Steven Yea was born in Inchon, South Korea, raised in Los Angeles, CA, and educated at Yale University, CT, and the Mount Sinai School of Medicine, NY. Scott L. Friedman, Steven's mentor, was born and raised in New York City, NY, and educated at Rensselaer Polytechnic Institute, NY, and the Mount Sinai School of Medicine, NY.