Silencing of the transcription factor KLF6 by siRNA leads to cell cycle arrest and sensitizes cells to apoptosis induced by DNA damage.

D’ASTOLFO D.; GEHRAU R.; ANDREOLI V.; BOCCO JL; KORITSCHONER N.

Hotel Amancay – Bariloche – Province of Río Negro – Argentina

Congreso; Combined meetings: Gene Expression and RNA Processing – Cell Biology, Signaling and Alternative Splicing; 2007

International Centre for Genetic Engineering and Biotechnology (ICGEB) - Facultad de Ciencias Exactas y

Kruppel-like factor 6 (KLF6) belongs to a large family of mammalian Sp1-like/KLF transcription factors that play critical roles in regulating key cellular functions ranging from differentiation to proliferation and apoptosis. KLF6 is an evolutionarily conserved and ubiquitously expressed protein that was originally identified as an activator of pregnancy specific genes. Initial evidence has implicated KLF6 as a tumor suppressor gene, which was found to be the subject of frequent somatic mutations in certain carcinomas. Given its potential role as a tumor suppressor gene, much effort has gone into determining altered KLF6 genotypes. Results have been rather controversial since a number of studies established that genetic alterations of KLF6 were infrequently observed in distinct types of human cancers (see Lievre et al.11 and references therein). More significantly, a recent study in mice indicated that targeted inactivation of KLF6 was lethal and severely impaired the proliferation rate of embryonic stem cells.12 The phenotype observed in KLF6-/- mice and stem cells strongly suggests that endogenous KLF6 is required for cell cycle progression, thereby contrasting with its potential tumor-suppressive activity. In view of the central role of KLF6 as a key factor in regulating cell growth, we aimed at elucidating the impact of endogenous KLF6 on cell proliferation and apoptosis by successfully applying approaches that employ DNA-damaging drugs and RNA interference.

These data clearly demonstrated that KLF6 loss by siRNAs increased the sub-G1 apoptotic cell population, which in turn correlated directly with nuclear DNA fragmentation. In addition, controlled overexpression of KLF6 protected HeLa cells from cisplatin-induced apoptosis.