The tumor suppressor, microRNA-34 (miR-34), a transcriptional target of TP53, functions in a positive feedback loop to activate TP53. Although miR-34 can inhibit cancer cells carrying TP53 mutations, this feedback to TP53 may be a prerequisite for full miR-34 function and may restrict its therapeutic application to patients with intact TP53. To investigate the functional relationships between TP53 and miR-34, and that of other TP53-regulated miRNAs including miR-215/192, we have used a panel of isogenic cancer cell lines that differ only with respect to their endogenous TP53 status. miR-34-induced inhibition of cancer cell growth is the same in TP53-positive and TP53-negative cells. In contrast, miR-215/192 functions through TP53. In the absence of TP53, miR-34, but not miR-215/192, is sufficient to induce an upregulation of the cell cycle-dependent kinase inhibitor p21 CIP1/WAF1. We identify histone deacetylase 1 (HDAC1) as a direct target of miR-34 and demonstrate that repression of HDAC1 leads to an induction of p21 CIP1/WAF1 and mimics the miR-34 cellular phenotype. Depletion of p21 CIP1/WAF1 specifically interferes with the ability of miR-34 to inhibit cancer cell proliferation. The data suggest that miR-34 controls a tumor suppressor pathway previously reserved for TP53 and provides an attractive therapeutic strategy for cancer patients irrespective of TP53 status. © The American Society of Gene and Cell Therapy.
CITATION STYLE
Zhao, J., Lammers, P., Torrance, C. J., & Bader, A. G. (2013). TP53-independent function of miR-34a via HDAC1 and p21 CIP1/WAF1. Molecular Therapy, 21(9), 1678–1686. https://doi.org/10.1038/mt.2013.148
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