Kruppel-like Pluripotency Factors As Modulators of Cancer Cell Therapeutic Responses

Tumor cells inherit from their normal precursors an extensive stress response machinery that is critical for survival in response to challenges including oxidative stress, wounding, and shear stress. Kruppel-like transcription factors, including KLF4 and KLF5, are rarely affected by genetic alteration during tumorigenesis, but compose key components of the stress response machinery in normal and tumor cells and interact with critical survival pathways, including RAS, p53, survivin, and the BCL2 family of cell death regulators. Within tumor cells, KLF4 and KLF5 play key roles in tumor cell fate, regulating cell proliferation, cell survival, and the tumor-initiating properties of cancer stem-like cells. These factors can be preferentially expressed in embryonic stem cells or cancer stem-like cells. Indeed, specific KLFs represent key components of a cross-regulating pluripotency network in embryonic stem cells and induce pluripotency when coexpressed in adult cells with other Yamanaka factors. Suggesting analogies between this pluripotency network and the cancer cell adaptive reprogramming that occurs in response to targeted therapy, recent studies link KLF4 and KLF5 to adaptive prosurvival signaling responses induced by HER2-targeted therapy. We review literature supporting KLFs as shared mechanisms in stress adaptation and cellular reprogramming and address the therapeutic implications. Cancer Res; 76(7); 1677-82. ©2016 AACR.