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
a Department of Biology; University of São Paulo State ; São Paulo , Brazil.
Epigenetics. 2015;10(7):622-32. doi: 10.1080/15592294.2015.1050173.
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.
神经丝重链多肽（NEFH）最近被确定为功能性乳腺癌高甲基化组中一个候选的DNA高甲基化基因。NEFH与神经丝中链多肽（NEFM）和神经丝轻链多肽（NEFL）形成复合物，进而构成神经丝，而神经丝是成熟神经元细胞骨架的结构成分。最近的研究报道了这些蛋白质在几种恶性肿瘤中表达失调，这表明神经丝可能在其他细胞类型中也发挥作用。我们采用综合方法，研究了乳腺癌中神经丝基因的表观遗传失活及其功能意义。我们报告称，乳腺癌中NEFH、NEFL和NEFM的DNA甲基化相关沉默很常见，具有癌症特异性，且与疾病进展的临床特征相关。这些基因的DNA甲基化介导的失活在包括胰腺、胃和结肠在内的多种其他癌症组织学类型中也会发生。神经丝复合物的主要亚基NEFH功能的恢复会降低乳腺癌细胞的增殖和生长，并使它们停滞在细胞周期的G0/G1期，同时减少迁移和侵袭。这些发现表明，DNA甲基化介导的神经丝基因NEFH、NEFM和NEFL的沉默是常见事件，可能促进乳腺癌以及其他恶性肿瘤的进展。
