Tumor Suppressor Activity of KLF6 Transcription Factor in Oncogenesis Triggered by H-Ras

TRUCCO, L; NICOLA, JP; SORIA, G; BOCCO, JL

Rosario

Congreso; L Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2014

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

KLF6 is a member of the Krüppel-like/Sp1 family of transcriptional regulators whose loss of function has beenassociated to cancer development. We have reported that endogenous KLF6 expression is induced by oncogenic Ras(H-RasG12V). However, KLF6 silencing did not modify the malignant phenotype triggered by H-RasG12V asdetermined by colony formation assays and tumor development in immunodeficient mice. This result indicates thatKLF6 is dispensable for H-RasG12V-mediated tumorigenesis but instead is suggesting that KLF6 induction could bepart of a failsafe mechanism of cells undergoing oncogenic activation, which is overriden by the dominant activity ofH-RasG12V. Thus, silencing endogenous KLF6 levels in NIH3T3 cells allows cell growth in the absence of serum,formation of transformed foci and generation of spontaneous tumors upon xenotransplantation in nude mice. Theseresults correlate with a significant reduction of p21 expression. Conversely, KLF6 overexpression produces a G1 cellcycle arrest, which can be resumed by siRNA-mediated decrease of p21. Finally, KLF6 overexpressionsignificantly hinders tumorigenesis triggered by H-RasG12V through a mechanism involving JNK activity and p21 upregulation. Hence, our data provides evidence about a KLF6 function in a tumor surveillance system that isactivated by oncogenic stress, playing an important role in tumor suppression.