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The human  ether-à-go-go -1 (h-eag1) K +  channel is expressed in a variety of cell lines derived from human malignant tumors and in clinical samples of several different cancers, but is otherwise absent in normal tissues. It was found to be necessary for cell cycle progression and tumorigenesis. Specific inhibition of h- eag1  expression leads to inhibition of tumor cell proliferation. We report here that h-eag1 expression is controlled by the p53− miR-34 −E2F1 pathway through a negative feed-forward mechanism. We first established E2F1 as a transactivator of h- eag1  gene through characterizing its promoter region. We then revealed that  miR-34 , a known transcriptional target of p53, is an important negative regulator of h-eag1 through dual mechanisms by directly repressing h-eag1 at the post-transcriptional level and indirectly silencing h- eag1  at the transcriptional level via repressing E2F1. There is a strong inverse relationship between the expression levels of  miR-34  and h-eag1 protein. H- eag1 antisense antagonized the growth-stimulating effects and the upregulation of h-eag1 expression in SHSY5Y cells, induced by knockdown of  miR-34 , E2F1 overexpression, or inhibition of p53 activity. Therefore, p53 negatively regulates h-eag1 expression by a negative feed-forward mechanism through the p53− miR-34 −E2F1 pathway. Inactivation of p53 activity, as is the case in many cancers, can thus cause oncogenic overexpression of h-eag1 by relieving the negative feed-forward regulation. These findings not only help us understand the molecular mechanisms for oncogenic overexpression of h-eag1 in tumorigenesis but also uncover the cell-cycle regulation through the p53− miR-34 −E2F1−h-eag1 pathway. Moreover, these findings place h-eag1 in the p53− miR-34 −E2F1−h-eag1 pathway with h-eag as a terminal effecter component and with  miR-34  (and E2F1) as a linker between p53 and h-eag1. Our study therefore fills the gap between p53 pathway and its cellular function mediated by h-eag1.

Transcriptional and Post-Transcriptional Mechanisms for Oncogenic Overexpression of Ether À Go-Go K+ Channel