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

被引:32
作者
Calmon, Marilia Freitas [1 ,2 ,3 ]
Jeschke, Jana [2 ,3 ,4 ]
Zhang, Wei [3 ]
Dhir, Mashaal [2 ]
Siebenkaes, Cornelia [2 ]
Herrera, Alexander [2 ]
Tsai, Hsing-Chen [3 ]
O'Hagan, Heather M. [3 ]
Pappou, Emmanouil P. [2 ]
Hooker, Craig M. [3 ]
Fu, Tao [2 ]
Schuebel, Kornel E. [3 ]
Gabrielson, Edward [5 ]
Rahal, Paula [1 ]
Herman, James G. [3 ]
Baylin, Stephen B. [3 ]
Ahuja, Nita [2 ,3 ,6 ]
机构
[1] Univ Sao Paulo State, Dept Biol, Sao Paulo, Brazil
[2] Johns Hopkins Univ, Dept Surg, Baltimore, MD USA
[3] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21205 USA
[4] Univ Libre Bruxelles, Lab Canc Epigenet, Fac Med, Brussels, Belgium
[5] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA
[6] Johns Hopkins Univ, Dept Urol, Baltimore, MD USA
关键词
breast cancer; DNA methylation; NEFH; NEFL; NEFM; TCGA; DNA HYPERMETHYLATION; COLORECTAL-CANCER; INTERMEDIATE-FILAMENTS; HISTONE MODIFICATIONS; CELL CARCINOMA; METHYLATION; HETEROZYGOSITY; INACTIVATION; EXPRESSION; BIOMARKERS;
D O I
10.1080/15592294.2015.1050173
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:622 / 632
页数:11
相关论文
共 45 条
  • [1] Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma
    Alholle, Abdullah
    Brini, Anna T.
    Gharanei, Seley
    Vaiyapuri, Sumathi
    Arrigoni, Elena
    Dallol, Ashraf
    Gentle, Dean
    Kishida, Takeshi
    Hiruma, Toru
    Avigad, Smadar
    Grimer, Robert
    Maher, Eamonn R.
    Latif, Farida
    [J]. EPIGENETICS, 2013, 8 (11) : 1198 - 1204
  • [2] Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene
    Bachman, KE
    Park, BH
    Rhee, I
    Rajagopalan, H
    Herman, JG
    Baylin, SB
    Kinzler, KW
    Vogelstein, B
    [J]. CANCER CELL, 2003, 3 (01) : 89 - 95
  • [3] A decade of exploring the cancer epigenome - biological and translational implications
    Baylin, Stephen B.
    Jones, Peter A.
    [J]. NATURE REVIEWS CANCER, 2011, 11 (10) : 726 - 734
  • [4] DNA methylation epigenotypes in breast cancer molecular subtypes
    Bediaga, Naiara G.
    Acha-Sagredo, Amelia
    Guerra, Isabel
    Viguri, Amparo
    Albaina, Carmen
    Ruiz Diaz, Irune
    Rezola, Ricardo
    Jesus Alberdi, Maria
    Dopazo, Joaquin
    Montaner, David
    de Renobales, Mertxe
    Fernandez, Agustin F.
    Field, John K.
    Fraga, Mario F.
    Liloglou, Triantafillos
    de Pancorbo, Marian M.
    [J]. BREAST CANCER RESEARCH, 2010, 12 (05):
  • [5] DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes
    Clements, Eriko G.
    Mohammad, Helai P.
    Leadem, Benjamin R.
    Easwaran, Hariharan
    Cai, Yi
    Van Neste, Leander
    Baylin, Stephen B.
    [J]. NUCLEIC ACIDS RESEARCH, 2012, 40 (10) : 4334 - 4346
  • [6] A comprehensive overview of Infinium HumanMethylation450 data processing
    Dedeurwaerder, Sarah
    Defrance, Matthieu
    Bizet, Martin
    Calonne, Emilie
    Bontempi, Gianluca
    Fuks, Francois
    [J]. BRIEFINGS IN BIOINFORMATICS, 2014, 15 (06) : 929 - 941
  • [7] Dedeurwaerder S, 2011, EPIGENOMICS-UK, V3, P771, DOI [10.2217/epi.11.105, 10.2217/EPI.11.105]
  • [8] Neurofilament Heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response
    Dubrowinskaja, Natalia
    Gebauer, Kai
    Peters, Inga
    Hennenlotter, Joerg
    Abbas, Mahmoud
    Scherer, Ralph
    Tezval, Hossein
    Merseburger, Axel S.
    Stenzl, Arnulf
    Grunwald, Viktor
    Kuczyk, Markus A.
    Serth, Juergen
    [J]. CANCER MEDICINE, 2014, 3 (02): : 300 - 309
  • [9] A DNA hypermethylation module for the stem/progenitor cell signature of cancer
    Easwaran, Hariharan
    Johnstone, Sarah E.
    Van Neste, Leander
    Ohm, Joyce
    Mosbruger, Tim
    Wang, Qiuju
    Aryee, Martin J.
    Joyce, Patrick
    Ahuja, Nita
    Weisenberger, Dan
    Collisson, Eric
    Zhu, Jingchun
    Yegnasubramanian, Srinivasan
    Matsui, William
    Baylin, Stephen B.
    [J]. GENOME RESEARCH, 2012, 22 (05) : 837 - 849
  • [10] EMI M, 1992, CANCER RES, V52, P5368