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

TRUCCO L.D.; NICOLA J.P.; SORIA G.; BOCCO J.L.

Rosario

Congreso; L Reunión Anual SAIB 2014; 2014

SAIB

KLF6 is a member of the Krüppel-like/Sp1 family of transcriptional regulators whose loss of function has been associated 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 as determined by colony formation assays and tumor development in immunodeficient mice. This result indicates that KLF6 is dispensable for H-RasG12V-mediated tumorigenesis but instead is suggesting that KLF6 induction could be part of a failsafe mechanism of cells undergoing oncogenic activation, which is override by the dominant activity of H-RasG12V. Thus, silencing endogenous KLF6 levels in NIH3T3 cells allow cell growth in the absence of serum, formation of transformed foci and generation of spontaneous tumors upon xenotransplantation in nude mice. These results correlate with a significant reduction of the p21 expression. Conversely, KLF6 overexpression produces a G1 cell cycle arrest which can be resumed by siRNA-mediated decrease of p21. Finally, KLF6 overexpression significantly 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 is activated by oncogenic stress, playing an important role in tumor suppression.