A novel role of KLF6 activity in the induction of cellular senescence and genome integrity maintenance.

MARÍA EUGENIA SABATINO; MARÍA FLORENCIA PANSA; IRIS A. GARCÍA; SOFÍA CARBAJOSA; FLORENCIA VILLAFAÑEZ; GASTÓN SORIA; JOSÉ LUIS BOCCO

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 inthe regulation of relevant biological processes as cell proliferation,differentiation and apoptosis. In addition, KLF6 have a tumor suppressoractivity and, accordingly, loss-of-functions mutations ofklf6 gene have been found in many human malignancies. We havedemonstrated that KLF6 knockdown leads to spontaneous transformationof fibroblast cells whereas forced KLF6 expression provokesa marked cell cycle arrest. In this regard, we hypothesized whetherKLF6-mediated cell cycle arrest could be associated with inductionof cellular senescence. In fact, this process limits proliferation of potentiallydetrimental cells, preventing tumorigenesis and restrainingtissue damaging helping to avoiding neoplastic transformation. In this study, we observed that increased expression levels of KLF6in HeLa cervical carcinoma cells was able to promote cellular senescence(Fisher Test, p<0,05), as determined by higher levelsof senescence associated β-galactosidase activity. Then, cellularsenescence induced by H2O2 treatment of NIH3T3 fibroblast cellswas markedly reduced upon KLF6 downregulation by stable shRNAtransduction (p<0,05). In addition to cellular senescence bypass,these cells also shown signs of genome instability as micronucleiand chromosome rings formation, suggesting that KLF6 may be involvedin genome integrity maintenance. These surprising findings,along with the cytostatic function of KLF6 upon oncogenic activationis suggesting that its tumor suppressor activity could be mediated bycellular senescence as an alarm signal in response to certain stimuliproducing exacerbated proliferation or cell transformation.