ETV4 interacts with LOXL2 to induce epigenetic activation of NID1 during colorectal cancer progression

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide and its poor prognosis is mainly caused by metastasis. Although extensive studies, the potential molecular mechanisms of CRC metastasis are not fully understood. In the present study, we found that ETV4 was remarkably upregulated in CRC and its overexpression correlated with lymph node metastasis. ETV4 could significantly promote the growth, epithelial-mesenchymal transition (EMT) and metastasis of CRC cells in vitro and in vivo. Mechanistic investigations found that LOXL2 was a novel transcriptional target and a direct interacting partner of ETV4 and was vital to ETV4-induced CRC malignant phenotypes. Further studies revealed that ETV4/LOXL2 complex could bind NID1 promoter to mediate its demethylation, induce NID1 expression and subsequent ERK signaling pathway activation, which is required for ETV4/LOXL2-mediated EMT and metastasis of CRC. Meanwhile, the expression of ETV4 and LOXL2 were significantly negatively correlated with the methylation of NID1 promoter in clinical samples. Besides, the combined ETV4, LOXL2 and NID1 as prognostic markers is more reliable than any one alone. Taken together, in this study, we demonstrated that ETV4 played a critical role in CRC metastasis, and unraveled the novel regulatory axis of ETV4/LOXL2/NID1, which contributed to the malignant progression of CRC.