A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth.

Publication Type:

Journal Article


The Biochemical journal, Volume 435, Issue 2, p.529-37 (2011)


Animalsdigestive disease, digestive deseases Cell Proliferationdigestive disease, digestive deseases Cell Transformation, Neoplasticdigestive disease, digestive deseases Cells, Cultureddigestive disease, digestive deseases Gene Expression Regulation, Neoplasticdigestive disease, digestive deseases Genes, rasdigestive disease, digestive deseases Genes, Tumor Suppressordigestive disease, digestive deseases Genetic Association Studiesdigestive disease, digestive deseases High-Throughput Screening Assaysdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Kruppel-Like Transcription Factorsdigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred C57BLdigestive disease, digestive deseases Mice, Nudedigestive disease, digestive deseases Multigene Familydigestive disease, digestive deseases NIH 3T3 Cellsdigestive disease, digestive deseases Sp Transcription Factors


SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.