TUMOR SUPPRESSOR AND ANTI-APOPTOTIC ACTIVITIES OF KLF6: A DOUBLE-EDGED SWORD IN TUMORIGENESIS

TRUCCO L.D.; NICOLA J.P.; MACCIONI M.; BOCCO J.L.

Miami

Simposio; Miami Winter Symposium 2015: Towards Personalized Cancer Medicine; 2015

Elsevier

KLF6 is a member of the Krüppel-like/Sp1 transcription factors family which have diverse roles in cellular differentiation, development, proliferation, signal transduction and apoptosis. KLF6 is ubiquitously expressed and mutations or downregulation of klf6 gene have been described in several human cancers, suggesting a tumor suppressor function. We have reported that endogenous KLF6 expression is induced by oncogenic Ras (H-RasG12V). However, KLF6 knock-down did not compromise the malignant phenotype triggered by H-RasG12V as determined by colony formation assays and xenograft experiments. Conversely, we found that KLF6 downregulation predisposes to spontaneous cellular transformation and increases the tumorigenic potential of NIH3T3 cells, associated with a reduced expression of the CDK inhibitor p21. Moreover, KLF6 overexpression significantly hinders the growth of H-RasG12V-driven tumors through a mechanism involving Jun N-terminal Kinase activity and upregulation of p21. We also demonstrated that ectopic KLF6 expression induced a G1-phase cell cycle arrest, which can be resumed by shRNA-mediated decrease of p21. This cytostatic response was associated with resistance to apoptosis mediated by DNA damaging chemotherapy drugs. Hence, our results indicate that even though KLF6 is dispensable for H-RasG12V-mediated transformation, also suggest that KLF6 induction could be part of a failsafe mechanism of cells undergoing oncogenic activation, and also contributes to the survival of transformed cells.