title: Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer.
abstract: 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.
authors.affiliation: a Department of Biology; University of São Paulo State ; São Paulo , Brazil.
authors.forename: Marilia Freitas
authors.initials: MF
authors.lastname: Calmon
authors.forename: Jana
authors.initials: J
authors.lastname: Jeschke
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Mashaal
authors.initials: M
authors.lastname: Dhir
authors.forename: Cornelia
authors.initials: C
authors.lastname: Siebenkäs
authors.forename: Alexander
authors.initials: A
authors.lastname: Herrera
authors.forename: Hsing-Chen
authors.initials: HC
authors.lastname: Tsai
authors.forename: Heather M
authors.initials: HM
authors.lastname: O'Hagan
authors.forename: Emmanouil P
authors.initials: EP
authors.lastname: Pappou
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hooker
authors.forename: Tao
authors.initials: T
authors.lastname: Fu
authors.forename: Kornel E
authors.initials: KE
authors.lastname: Schuebel
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.forename: Paula
authors.initials: P
authors.lastname: Rahal
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007382:Intermediate Filaments / Q000473:pathology; D016900:Neurofilament Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L; C051774:neurofilament protein H; C061195:neurofilament protein M
keywords: DNA methylation; NEFH; NEFL; NEFM; TCGA; breast cancer