title: TP53-independent function of miR-34a via HDAC1 and p21(CIP1/WAF1.).
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.
authors.affiliation: Mirna Therapeutics, Inc., Austin, Texas 78744, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Zhao
authors.forename: Paul
authors.initials: P
authors.lastname: Lammers
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Torrance
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Bader
mesh_terms: D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004794:Enzyme Repression; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000627:therapeutic use*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1