@article{a1488ef1256248fb8a8abb0baae93ce2,
title = "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.",
author = "Towers, {Christina G.} and Guarnieri, {Anna L.} and Micalizzi, {Doug S.} and Harrell, {J. Chuck} and Gillen, {Austin E.} and Jihye Kim and Wang, {Chu An} and Oliphant, {Michael U.J.} and Drasin, {David J.} and Guney, {Michelle A.} and Peter Kabos and Sartorius, {Carol A.} and Tan, {Aik Choon} and Perou, {Charles M.} and Espinosa, {Joaquin M.} and Ford, {Heide L.}",
note = "Funding Information: We are grateful to Christine Childs from the Flow Cytometry Shared Resource of the University of Colorado Comprehensive Cancer Center for her help with experimental analysis. We would also like to thank members of the Genomics and Microarray Shared Resource of the University of Colorado Cancer Center (P30CA046934) for their help with array analysis. We acknowledge Deepika Neelakantan for technical assistance and Adam Pfefferle for assistance with data normalization on gene arrays. We are grateful to John Tentler for providing the RKO and HCT-116 parental cell lines. We would also like to thank Jeff Kieft with assistance and advice regarding mechanisms of translation regulation, and all members of the Ford laboratory for helpful comments and suggestions. This work was funded by grants from The National Cancer Institute (R01-CA095277 and R01-CA157790) to H.L.F. C.G.T. was funded by the UC Denver AMC Molecular Biology Program T32 training grant, NIH-RO1 Diversity Supplement to R01-CA157790, and the UNCF/MERCK Graduate Fellowship. A.L.S. and J.M.E. were supported by an NRSA F32 from the NIH (1F32CA199716-01), NIH grant RO1CA117907, Leukemia and Lymphoma Society grant NIA8996-14 and the Howard Hughes Medical Institute. J.C.H. and C.M.P. were funded by NCI Breast SPORE program (P50-CA58223-09A1), RO1-CA148761, and by the Triple Negative Breast Cancer Foundation. C.-A.W., D.S.M. and A.L.G. were funded by predoctoral fellowships from the Department of Defense Breast Cancer Research Program (W81ZWH-10-1-0162, W81XWH-06-1-0757, W81XWH-10-1-0296). D.J.D. was funded by an NRSA from the NCI (F31-CA165617). P.K. and M.A.G. supported by grants from the Grohne Cancer Research Fund ASCO Young Investigator Award, the National Institutes of Health CA164048. C.A.S. was supported by NIH/NCI 1R01CA140985.",
year = "2015",
month = dec,
day = "21",
doi = "10.1038/ncomms10077",
language = "English",
volume = "6",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}