| Title | Ras promotes growth by alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma. | | Author(s) | Yea S, Narla G, Zhao X, Garg R, Tal-Kremer S, Hod E, Villanueva A, Loke J, Tarocchi M, Akita K, Shirasawa S, Sasazuki T, Martignetti JA, Llovet JM, Friedman SL | | Institution | Division of Liver Diseases and Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA. | | Source | Gastroenterology 2008 May; 134(5):1521-31. | | MeSH | Blotting, Western
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
Genes, ras
Humans
Kruppel-Like Transcription Factors
Liver Neoplasms
Mutation
Polymerase Chain Reaction
Promoter Regions (Genetics)
Protein Isoforms
Proto-Oncogene Proteins
RNA, Neoplasm
Signal Transduction
Tumor Suppressor Proteins
| | Abstract | BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer worldwide and the third most lethal. Dysregulation of alternative splicing underlies a number of human diseases, yet its contribution to liver cancer has not been explored fully. The Krüppel-like factor 6 (KLF6) gene is a zinc finger transcription factor that inhibits cellular growth in part by transcriptional activation of p21. KLF6 function is abrogated in human cancers owing to increased alternative splicing that yields a dominant-negative isoform, KLF6 splice variant 1 (SV1), which antagonizes full-length KLF6-mediated growth suppression. The molecular basis for stimulation of KLF6 splicing is unknown.
METHODS: In human HCC samples and cell lines, we functionally link oncogenic Ras signaling to increased alternative splicing of KLF6 through signaling by phosphatidylinositol-3 kinase and Akt, mediated by the splice regulatory protein ASF/SF2.
RESULTS: In 67 human HCCs, there is a significant correlation between activated Ras signaling and increased KLF6 alternative splicing. In cultured cells, Ras signaling increases the expression of KLF6 SV1, relative to full-length KLF6, thereby enhancing proliferation. Abrogation of oncogenic Ras signaling by small interfering RNA (siRNA) or a farnesyl-transferase inhibitor decreases KLF6 SV1 and suppresses growth. Growth inhibition by farnesyl-transferase inhibitor in transformed cell lines is overcome by ectopic expression of KLF6 SV1. Down-regulation of the splice factor ASF/SF2 by siRNA increases KLF6 SV1 messenger RNA levels. KLF6 alternative splicing is not coupled to its transcriptional regulation.
CONCLUSIONS: Our findings expand the role of Ras in human HCC by identifying a novel mechanism of tumor-suppressor inactivation through increased alternative splicing mediated by an oncogenic signaling cascade. | | Language | eng | | Pub Type(s) | Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
| | PubMed ID | 18471523 |
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