Research Papers:

N6-methyladenosine contributes to cellular phenotype in a genetically-defined model of breast cancer progression

Nate J. Fry, Brittany A. Law, Olga R. Ilkayeva, Kristen R. Carraway, Christopher L. Holley and Kyle D. Mansfield _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:31231-31243. https://doi.org/10.18632/oncotarget.25782

Metrics: PDF 2041 views  |   HTML 2787 views  |   ?  


Nate J. Fry1, Brittany A. Law2, Olga R. Ilkayeva3, Kristen R. Carraway1, Christopher L. Holley2 and Kyle D. Mansfield1

1Biochemistry and Molecular Biology Department, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA

2Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA

3Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA

Correspondence to:

Kyle D. Mansfield, email: [email protected]

Keywords: N6-methyladenosine; hypoxia; breast cancer; transformation; RNA modification

Received: May 22, 2018     Accepted: July 05, 2018     Published: July 27, 2018


The mRNA modification N6-methyladenosine (m6A) is involved in many post-transcriptional regulatory processes including mRNA stability and translational efficiency. However, it is also imperative to correlate these processes with phenotypic outputs during cancer progression. Here we report that m6A levels are significantly decreased in genetically-defined immortalized and oncogenically-transformed human mammary epithelial cells (HMECs), as compared with their primary cell predecessor. Furthermore, the m6A methyltransferase (METTL3) is decreased and the demethylase (ALKBH5) is increased in the immortalized and transformed cell lines, providing a possible mechanism for this basal change in m6A levels. Although the immortalized and transformed cells showed lower m6A levels than their primary parental cell line, overexpression of METTL3 and METTL14, or ALKBH5 knockdown to increase m6A levels in transformed cells increased proliferation and migration. Remarkably, these treatments had little effect on the immortalized cells. Together, these results suggest that m6A modification may be downregulated in immortalized cells as a brake against malignant progression. Finally, we found that m6A levels in the immortalized and transformed cells increased in response to hypoxia without corresponding changes in METTL3, METTL14 or ALKBH5 expression, suggesting a novel pathway for regulation of m6A levels under stress.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25782