Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer
Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer
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DOI：
10.1158/0008-5472.can-14-3816
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发表时间：
2016-04-01
期刊：
影响因子：
11.2
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
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作者：
Ando, Mizuo;Kawazu, Masahito;Mano, Hiroyuki
ELF 4（也称为MEF）是ETS转录因子家族的成员。ELF 4的致癌作用已在造血系统恶性肿瘤中得到证实，但其在上皮肿瘤中的功能仍不清楚。在这里，我们表明，ELF4可以作为一种肿瘤抑制因子，并在广泛的人类肿瘤体细胞失活。我们发现了一个错义突变，影响ELF4在口腔鳞状细胞癌细胞中的反式激活潜力。通过引入野生型ELF4恢复反式激活活性显著抑制体外细胞增殖和肿瘤异种移植物生长。此外，我们发现ELF 1和ELF 2，与ELF 4密切相关的转录因子，也在多种癌细胞系中发挥抗增殖作用。ELF1和ELF2的突变与ELF4一样，在人类癌症中广泛存在，但几乎都是相互排斥的。此外，染色质免疫沉淀结合高通量测序揭示了ELF4结合位点的基因组区域与细胞周期调控和凋亡相关的基因相邻。最后，我们提供的机制证据表明，ELF4的抗增殖作用介导的诱导HRK，细胞凋亡的激活剂，和DLX3，细胞生长的抑制剂。总的来说，我们的研究结果揭示了一种新的人类癌症亚型，其特征在于ELF亚家族蛋白质的失活突变，并保证进一步研究ELF恢复可能具有治疗益处的特定环境。
ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted anti-proliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial.