EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression

Kaname Sakamoto,Keisuke Masuyama,Takashi Ando,Tomonori Kawasaki,Jiro Ichikawa,Yujiro Kimura,Hiroki Ishii,Keiji Miyazawa,Kou Kayamori,Kaori Endo,Ryosuke Nakamura,Tomoyuki Kawataki,Masao Saitoh,Shogo Ehata,Kei Sakamoto,Kunio Yoshizawa,Kunio Miyake

doi: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.

Highlights

Squamous cell carcinoma is the predominant tumor type in head and neck cancer
epithelial–mesenchymal transition (EMT) phenotypes in head and neck squamous cell carcinoma (HNSCC) cell lines We previously reported that ZEB1/2 (ZEB1 and ZEB2)
Among the various HNSCC cell lines, we found that TSU and HOC313 cells, similar to MDA-MB-231 cells, express high levels of vimentin and ZEB1/2, and low levels of Ecadherin, while other HNSCC cells, similar to MCF7 cells, expressed high levels of E-cadherin and low levels of vimentin and ZEB1/2 (Fig. 1A, B and data not shown)

Summary

Introduction

Squamous cell carcinoma is the predominant tumor type in head and neck cancer. Two-thirds of patients with head and neck squamous cell carcinoma (HNSCC) present local metastases in bones and regional lymph nodes during their first visit to a hospital, and are diagnosed as advanced stages[1]. K.a. ESE1), ELF5 (a.k.a. ESE2), and EHF (a.k.a. ESE3)[11]. ELF3 gene amplification occurs in various kinds of cancers, and ELF3 mutations frequently found in ampullary adenocarcinomas are heterozygous, suggesting that ELF3 may act as a haploinsufficient tumor suppressor[12]. Compared to ELF3, mutations in EHF are relatively rare in human cancers and are not frequently deposited in public datasets. Occasional mutation and amplification of EHF occurs in a subset of cancers, such as ovarian, stomach, and bladder cancer. Little is known about the roles of EHF in cancer[11]

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Conclusion