Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, whi...

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Bibliographic Details
Published in:Epigenetics 2015-07, Vol.10 (7), p.622-632
Main Authors: Calmon, Marilia Freitas, Jeschke, Jana, Zhang, Wei, Dhir, Mashaal, Siebenkäs, Cornelia, Herrera, Alexander, Tsai, Hsing-Chen, O'Hagan, Heather M, Pappou, Emmanouil P, Hooker, Craig M, Fu, Tao, Schuebel, Kornel E, Gabrielson, Edward, Rahal, Paula, Herman, James G, Baylin, Stephen B, Ahuja, Nita
Format: Article
Language:English
Subjects:
breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cell Cycle Checkpoints
Cell Line, Tumor
Disease Progression
DNA Methylation
Epigenesis, Genetic
Female
Gene Silencing
Humans
Intermediate Filaments - pathology
NEFH
NEFL
NEFM
Neurofilament Proteins - genetics
Promoter Regions, Genetic
Research Paper
TCGA
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Summary:Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, which are structural components of the cytoskeleton in mature neurons. Recent studies reported the deregulation of these proteins in several malignancies, suggesting that neurofilaments may have a role in other cell types as well. Using a comprehensive approach, we studied the epigenetic inactivation of neurofilament genes in breast cancer and the functional significance of this event. We report that DNA methylation-associated silencing of NEFH, NEFL, and NEFM in breast cancer is frequent, cancer-specific, and correlates with clinical features of disease progression. DNA methylation-mediated inactivation of these genes occurs also in multiple other cancer histologies including pancreas, gastric, and colon. Restoration of NEFH function, the major subunit of the neurofilament complex, reduces proliferation and growth of breast cancer cells and arrests them in Go/G1 phase of the cell cycle along with a reduction in migration and invasion. These findings suggest that DNA methylation-mediated silencing of the neurofilament genes NEFH, NEFM, and NEFL are frequent events that may contribute to the progression of breast cancer and possibly other malignancies.
ISSN:1559-2294
1559-2308
DOI:10.1080/15592294.2015.1050173