Dataset Information

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.

ABSTRACT: TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

SUBMITTER: Towers CG

PROVIDER: S-EPMC4703841 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.

Towers Christina G CG Guarnieri Anna L AL Micalizzi Doug S DS Harrell J Chuck JC Gillen Austin E AE Kim Jihye J Wang Chu-An CA Oliphant Michael U J MUJ Drasin David J DJ Guney Michelle A MA Kabos Peter P Sartorius Carol A CA Tan Aik-Choon AC Perou Charles M CM Espinosa Joaquin M JM Ford Heide L HL

Nature communications 20151221

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and preve ...[more]

PMID: 26687066

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Project description:MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and are described to influence differentiation as well as metabolic, endocrine, and inflammatory functions. We previously identified miR-27a being upregulated under inflammatory conditions in human adipocytes and aimed to elucidate its function in adipocyte biology. Both strands of miR-27a, miR-27a-3p and -5p, were downregulated during the adipogenic differentiation of Simpson-Golabi-Behmel syndrome (SGBS) cells, human multipotent adipose-derived stem cells (hMADS), and human primary adipose-derived stromal cells (hASCs). Using miRNA-mimic transfection, we observed that miR-27a-3p is a crucial regulator of adipogenesis, while miR-27a-5p did not alter the differentiation capacity in SGBS cells. In silico screening predicted lipoprotein lipase (LPL) and peroxisome proliferator activated receptor γ (PPARγ) as potential targets of miR-27a-3p. The downregulation of both genes was verified in vitro, and the interaction of miR-27-3p with target sites in the 3' UTRs of both genes was confirmed via a miRNA-reporter-gene assay. Here, the knockdown of LPL did not interfere with adipogenic differentiation, while PPARγ knockdown decreased adipogenesis significantly, suggesting that miR-27-3p exerts its inhibitory effect on adipogenesis by repressing PPARγ. Taken together, we identified and validated a crucial role for miR-27a-3p in human adipogenesis played by targeting the essential adipogenic transcription factor PPARγ. Though we confirmed LPL as an additional target of miR-27a-3p, it does not appear to be involved in regulating human adipogenesis. Thereby, our findings call the conclusions drawn from previous studies, which identified LPL as a crucial regulator for murine and human adipogenesis, into question.

Dataset Information

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.

Publications

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.

Similar Datasets

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