Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer

Aberrant regulation of the Wnt/beta-catenin pathway plays important roles in colorectal carcinogenesis, with over 90% of cases of sporadic colon cancer featuring beta-catenin accumulation. While ubiquitination-mediated degradation is widely accepted as a major route for beta-catenin protein turnover, little is known about the regulation of beta-catenin in transcriptional level. Here we show that Elf3, a member of the E-twenty-six family of transcription factors, drives beta-catenin transactivation and associates with poor survival of colorectal cancer (CRC) patients. We first found recurrent amplification and upregulation of Elf3 in CRC tissues, and further Gene Set Enrichment Analysis identified significant association between Elf3 expression and activity of WNT/beta-catenin pathway. Chromatin immunoprecipitation and electrophoretic mobility shift assay consistently revealed that Elf3 binds to and transactivates beta-catenin promoter. Ectopic expression of Elf3 induces accumulation of beta-catenin in both nucleus and cytoplasm, causing subsequent upregulation of several effector genes including c-Myc, VEGF, CCND1, MMP-7 and c-Jun. Suppressing Elf3 in CRC cells attenuates beta-catenin signaling and decreases cell proliferation, migration and survival. Targeting Elf3 in xenograft tumors suppressed tumor progression in vivo. Taken together, our data identify Elf3 as a pivotal driver for beta-catenin signaling in CRC, and highlight potential prognostic and therapeutic significance of Elf3 in CRC.