TP53-independent function of miR-34a via HDAC1 and p21 CIP1/WAF1

51Citations
Citations of this article
34Readers
Mendeley users who have this article in their library.

Abstract

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.

Cite

CITATION STYLE

APA

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

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free