Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

The mechanisms of colorectal cancer cell mesenchymal-epithelial transition induced by hepatocyte exosome-derived miR-203a-3p

Phosphatase of regenerating liver 3(PRL3)promotes colorectal cancer(CRC)metastasis by inducing epithelial-to-mesenchymal transition.Mesenchymal-to-epithelial transition(MET),the opposite of epithelial-to-mesenchymal transition,has been proposed as a mechanism for the establishment of metastatic neoplasms.However,the molecular mechanism of MET remains unclear.Here,we show that miR-203a-3p derived from hepatocyte exosomes inhibits Src expression,reduces epidermal growth factor receptor activity and downstream signaling pathways,and increases E-cadherin expression,which is a typical mesenchymal cell marker of MET,in CRC cells.These results show the important role of epidermal growth factor receptor in CRC cell MET.