The paradoxical behaviour of Krüppel-like Factor 4 (KLF4) - both a tumour-supressor or oncogenic, depending on the context - is given an explanation in the November 2005 issue of Nature Cell Biology.
KLF4 regulates genes involved in cell division and embryonic development, and has been implicated in gastro-intestinal cancer as a tumour suppressor. In other settings, such as breast cancer, KLF4 is overexpressed and positively contributes to tumorigenesis.
The team found that KLF4 allows cells to avoid senescence - a process of cellular ageing resulting in loss of cell division. However, KLF4 was also found to be a potent inhibitor of proliferation in normal non-senescing cells. This switch in behaviour is linked to several genes known to have key roles in cell growth and cancer. KLF4 represses the tumour suppressor p53, while at the same time activating the p21(CIP1) cell-cycle inhibitor. p21(CIP1) function is lost in most cancers. In this context the repression of p53 frees cells from the shackles of this important growth regulator to expose KLF4's hidden growth-promoting potential. This allows for cell transformation, as well as suppression of cell suicide, or apoptosis.
Depletion of KLF4 from breast cancer cells restored expression of the cancer surveillance gene p53 and allowed apoptosis to occur. These data show that overexpression of KLF4 and loss of p21(CIP1) co-operate in cancer formation. The study suggests that, depending on the setting, KLF4 is an enticing target for cancer therapy. However, in cases where p21(CIP1) is active, inhibition of KLF4 may actually promote cancer formation. This study is a striking example of the importance of thoroughly understanding the molecular role of cancer genes before designing therapeutic approaches.
Daniel S. Peeper (The Netherlands Cancer Institute, Amsterdam, The Netherlands)
Abstract available online.
(C) Nature Cell Biology press release.
Message posted by: Trevor M. D'Souza