Expression of the imprinted H19 gene is remarkably elevated in a large number of human cancers. Recently, we reported that H19 RNA is up-regulated in hypoxic stress and furthermore, it possesses oncogenic properties. However, the underlying mechanism(s) of these phenomena remain(s) unknown. Here we demonstrate a tight correlation between H19 RNA elevation by hypoxia and the status of the p53 tumor suppressor. Wild type p53 (p53wt) prevents the induction of H19 upon hypoxia, and upon its reconstitution in p53null cells. The last case is accompanied by a decrease in cell viability. The p53 effect is nuclear and seems independent of its tetramerization. Furthermore, using knockdown and over-expression approaches we identified HIF1-α as a critical factor that is responsible for H19 induction upon hypoxia. Knocking down HIF1-α abolishes H19 RNA induction, while its over-expression significantly enhances the H19 elevation in p53null hypoxic cells. In p53wt hypoxic cells simultaneous suppression of p53 and over-expression of HIF1-α are needed to induce H19 significantly, while each treatment separately resulting in a mild induction, indicating that the molecular mechanism of p53 suppression effect on H19 may at least in part involve interfering with HIF1-α activity. In vivo a significant increase in H19 expression occurred in tumors derived from p53null cells but not in p53wt cells. Taken together, our results indicate that a functional link exists between p53, HIF1-α and H19 that determines H19 elevation in hypoxic cancer cells. We suggest that this linkage plays a role in tumor development.
|Original language||American English|
|Number of pages||9|
|Journal||Biochimica et Biophysica Acta - Molecular Cell Research|
|State||Published - Apr 2010|
Bibliographical noteFunding Information:
This work is supported by the grants from the ISF , the FP6 program LSHB-CT-2004-512034 (MOLEDA), LSHB-CT-2005-018961 (INTHER) and the FP7 program LSHB-CT-2008-223317 (LIV-ES). Additional support was provided through grants from Barbara Fox Miller , Lille and Alfy Nathan , the Horowitz and the Wolfson Foundations .
- Cell viability
- H19 non-coding RNA
- Hypoxia-inducible factor alpha
- P53 tumor suppressor