A Novel Role of KLF6 Activity in the Induction of Cellular Senescence and Genome Integrity Maintenance

SABATINO M. E.; PANSA M. F.; GARCIA I.A.; CARBAJOSA S.; VILLAFAÑEZ M.F.; SORIA G.; BOCCO J.L.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias 2017; 2017

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Krüppel-like factor 6 (KLF6) is a transcription factor involved in the regulation of relevant biological processes as cell proliferation, differentiation and apoptosis. In addition, KLF6 have a tumor suppressor activity and, accordingly, loss-of-functions mutations of klf6 gene have been found in many human malignancies. We have demonstrated that KLF6 knockdown leads to spontaneous transformation of fibroblast cells whereas forced KLF6 expression provokes a marked cell cycle arrest. In this regard, we hypothesized whether KLF6-mediated cell cycle arrest could be associated with induction of cellular senescence. In fact, this process limits proliferation of potentially detrimental cells, preventing tumorigenesis and restraining tissue damaging helping to avoiding neoplastic transformation. In this study, we observed that increased expression levels of KLF6 in HeLa cervical carcinoma cells was able to promote cellular senescence (Fisher Test, p<0,05), as determined by higher levels of senescence associated β-galactosidase activity. Then, cellular senescence induced by H2O2 treatment of NIH3T3 fibroblast cells was markedly reduced upon KLF6 downregulation by stable shRNA transduction (p<0,05). In addition to cellular senescence bypass, these cells also shown signs of genome instability as micronuclei and chromosome rings formation, suggesting that KLF6 may be involved in genome integrity maintenance. These surprising findings, along with the cytostatic function of KLF6 upon oncogenic activation is suggesting that its tumor suppressor activity could be mediated by cellular senescence as an alarm signal in response to certain stimuli producing exacerbated proliferation or cell transformation.