期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10077
关键词
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资金
- National Cancer Institute [R01-CA095277, R01-CA157790]
- UNCF/MERCK Graduate Fellowship
- NRSA F32 from the NIH [1F32CA199716-01]
- NIH [RO1CA117907]
- Leukemia and Lymphoma Society [NIA8996-14]
- Howard Hughes Medical Institute
- NCI Breast SPORE program [P50-CA58223-09A1, RO1-CA148761]
- Triple Negative Breast Cancer Foundation
- Department of Defense Breast Cancer Research Program [W81ZWH-10-1-0162, W81XWH-06-1-0757, W81XWH-10-1-0296]
- NRSA from the NCI [F31-CA165617]
- Grohne Cancer Research Fund ASCO Young Investigator Award
- National Institutes of Health [CA164048]
- NIH/NCI [1R01CA140985]
- UC Denver AMC Molecular Biology Program T32 training grant, NIH [R01-CA157790]
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.
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