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 antiproliferative 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.
Cancer Res; 76(7); 1814-24. ©2016 AACR.