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

Year: 2020

Type: article

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.

Source: Carolina Digital Repository (University of North Carolina at Chapel Hill)

DOI: 10.17615/dnrn-cx42

Authors: Perou, Charles M., Ford, Heide L., Gillen, Austin E., Sartorius, Carol A., Guney, Michelle A., Tan, Aik-Choon, Espinosa, Joaquin M., Kim, Jihye, Kabos, Peter, Wang, Chu-An, Oliphant, Michael U.J., Drasin, David J.

Language: English

Topic: Cancer-related Molecular Pathways

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: U.S. Department of Defense, Leukemia and Lymphoma Society, American Society of Clinical Oncology, Triple Negative Breast Cancer Foundation, National Institutes of Health, University of Colorado Denver, Cancer Center, University of Colorado, National Institute on Aging, National Cancer Institute

OpenAlex ID: W4300005197