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

Christina G. Towers, Anna L. Guarnieri, Doug S. Micalizzi, J. Chuck Harrell, Austin E. Gillen, Jihye Kim, Chu An Wang, Michael U J Oliphant, David J. Drasin, Michelle A. Guney, Peter Kabos, Carol A. Sartorius, Aik-Choon Tan, Charles M. Perou, Joaquin M. Espinosa, Heide L. Ford

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Article number10077
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015 Dec 21
Externally publishedYes

Fingerprint

Tumor Suppressor Protein p53
Ribosomal Proteins
Oncogene Proteins
MicroRNAs
Down-Regulation
proteins
Tumors
tumors
cancer
Homeodomain Proteins
Neoplasms
regulators
mutations
therapy
drugs
interactions
Up-Regulation
Pharmaceutical Preparations
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Towers, C. G., Guarnieri, A. L., Micalizzi, D. S., Harrell, J. C., Gillen, A. E., Kim, J., ... Ford, H. L. (2015). The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nature Communications, 6, [10077]. https://doi.org/10.1038/ncomms10077

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. / Towers, Christina G.; Guarnieri, Anna L.; Micalizzi, Doug S.; Harrell, J. Chuck; Gillen, Austin E.; Kim, Jihye; Wang, Chu An; Oliphant, Michael U J; Drasin, David J.; Guney, Michelle A.; Kabos, Peter; Sartorius, Carol A.; Tan, Aik-Choon; Perou, Charles M.; Espinosa, Joaquin M.; Ford, Heide L.

In: Nature Communications, Vol. 6, 10077, 21.12.2015.

Research output: Contribution to journalArticle

Towers, CG, Guarnieri, AL, Micalizzi, DS, Harrell, JC, Gillen, AE, Kim, J, Wang, CA, Oliphant, MUJ, Drasin, DJ, Guney, MA, Kabos, P, Sartorius, CA, Tan, A-C, Perou, CM, Espinosa, JM & Ford, HL 2015, 'The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p', Nature Communications, vol. 6, 10077. https://doi.org/10.1038/ncomms10077
Towers CG, Guarnieri AL, Micalizzi DS, Harrell JC, Gillen AE, Kim J et al. The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nature Communications. 2015 Dec 21;6. 10077. https://doi.org/10.1038/ncomms10077
Towers, Christina G. ; Guarnieri, Anna L. ; Micalizzi, Doug S. ; Harrell, J. Chuck ; Gillen, Austin E. ; Kim, Jihye ; Wang, Chu An ; Oliphant, Michael U J ; Drasin, David J. ; Guney, Michelle A. ; Kabos, Peter ; Sartorius, Carol A. ; Tan, Aik-Choon ; Perou, Charles M. ; Espinosa, Joaquin M. ; Ford, Heide L. / The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. In: Nature Communications. 2015 ; Vol. 6.
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