EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression

• Main Authors: Kaname Sakamoto, Kaori Endo, Kei Sakamoto, Kou Kayamori, Shogo Ehata, Jiro Ichikawa, Takashi Ando, Ryosuke Nakamura, Yujiro Kimura, Kunio Yoshizawa, Keisuke Masuyama, Tomoyuki Kawataki, Kunio Miyake, Hiroki Ishii, Tomonori Kawasaki, Keiji Miyazawa, Masao Saitoh
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-03-01
• Series: Oncogenesis
• Online Access: https://doi.org/10.1038/s41389-021-00313-2

Abstract 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.