ETS homologous factor (EHF) belongs to the epithelium-specific subfamily of the E26 transformation-specific (ETS) transcription factor family. Currently, little is known about EHF’s function in cancer. We previously reported that ETS1 induces expression of the ZEB family proteins ZEB1/δEF1 and ZEB2/SIP1, which are key regulators of the epithelial–mesenchymal transition (EMT), by activating the ZEB1 promoters. We have found that EHF gene produces two transcript variants, namely a long form variant that includes exon 1 (EHF-LF) and a short form variant that excludes exon 1 (EHF-SF). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting the EMT phenotypes of cancer cells. Most importantly, we identified a novel point mutation within the conserved ETS domain of EHF, and found that EHF mutations abolish its original function while causing the EHF protein to act as a potential dominant negative, thereby enhancing metastasis in vivo. Therefore, we suggest that EHF acts as an anti-EMT factor by inhibiting the expression of ZEBs, and that EHF mutations exacerbate cancer progression.

ETS同源因子（EHF）属于E26转化特异性（ETS）转录因子家族的上皮特异性亚家族。目前，关于EHF在癌症中的功能知之甚少。我们以前曾报道过，ETS1通过激活ZEB1启动子来诱导ZEB家族蛋白ZEB1 /δEF1和ZEB2 / SIP1的表达，这是上皮-间质转化（EMT）的关键调节剂。我们已经发现，EHF基因产生两个转录物变体，即包括外显子1的长型变体（EHF-LF）和排除外显子1的短型变体（EHF-SF）。只有EHF-SF才能消除ETS1介导的ZEB1激活通过促进ETS1蛋白的降解而启动子，从而抑制癌细胞的EMT表型。最重要的是，我们在EHF的保守ETS结构域内鉴定了一个新的点突变，并发现EHF突变取消了其原始功能，同时使EHF蛋白充当潜在的显性负性突变，从而增强了体内转移。因此，我们建议EHF通过抑制ZEBs的表达而充当抗EMT因子，并且EHF突变会加剧癌症的进展。