There is no need to emphasize the overwhelming importance of p53 for crucial cellular processes and of genetic alterations resulting from its loss of function or a dominant oncogenic mutant in many human cancer types. These functions are well described and include control of cell cycle progression, apoptosis, senescence, DNA-repair mechanisms and autophagy [1]. A new page in the huge book of p53 was opened in a recent publication by Chang et al. by linking p53 to the control of an epithelial-mesenchymal transition (EMT) and its associated effects [2]. EMT is a key program in embryonic development and is conferred by so-called EMT activators, transcriptional repressors, such as Snail and ZEB family members, which suppress expression of epithelial genes. Its aberrant activation in cancer cells induces malignant tumor progression, invasion, dissemination and finally metastasis, due to acquisition of an abnormal cellular motility [3]. Recently, EMT was also linked to an activation of stemness properties, thereby conferring a combined stemness and motility phenotype to cancer cells [4]. Thus aberrant EMT might induce a subpopulation of “Migrating Cancer Stem Cells” as potential source of metastasis [5]. At molecular level EMT activators were shown to suppress transcription of all five members of the miR-200 family of microRNAs, located in two clusters on Chr. 1 (miR-200a, b and 429) and Chr. 12 (miR-141 and 200c)[6, 7]. In turn, miR-200 members inhibit translation of EMT-activators, particularly ZEB factors, thereby inducing the reverse process of a mesenchymal-epithelial transition (MET)[7-10]. Thus, miR-200 and ZEB1 factors are linked in a reciprocal feed-back loop, which controls an immense phenotypic flexibility and plasticity [11]. The range of this plasticity became clear, when it was shown that miR-200 not only counteracts classical EMT properties like cell motility, but also suppresses translation of stem cells factors, such as BMI1 [12, 13]. Accordingly, miR-200 family members were shown to be down-regulated in breast cancer stem cells and normal breast epithelial stem cells [12]. Due to the strong potency of miR-200 family members, in particular miR-200c, to control crucial cellular processes, such as motility and stemness, its own regulators play an important role. Although EMT activators, particularly ZEB factors, were already identified as transcriptional repressors of miR-200 genes, their activating pathways were still undefined. This gap was closed in the publication by Chang et al.[2], showing that p53 is a transcriptional activator of the miR-200c gene (Figure 1).

Knowing that miR-200 family members are down-regulated in the stem cell fraction of primary human mammary epithelial cells (HMECs), the authors looked for regulatory elements in the respective promoters. They detected p53 response elements in the common promoter of miR-141 and miR-200c (but not in the second cluster encoding miR-200a, b and 429) and validated a direct transcriptional activation by p53. Overexpression of p53 increased expression of miR-200c and reduced expression of its known targets BMI1, KLF4 and ZEB1. Importantly, along with a p53-dependent activation of miR-200c, stemness and EMT properties were suppressed. In contrast, shRNA-mediated depletion of p53 or inhibition of WT p53 expression by TGFβ treatment in MCF12A breast epithelial cells had the opposite effect. Is miR-200c an important effector of p53 functions? This was verified by showing that the consequences of p53 depletion on EMT and stemness could be rescued by overexpressing miR-200c. In contrast, the suppression of EMT and stemness by overexpressing WT p53 could …