LSD1 regulates the FOXF2-mediated Wnt/β-catenin signaling pathway by interacting with Ku80 to promote colon cancer progression.

Lysine-specific demethylase 1 (LSD1) is widely involved in the proliferation, invasion, and metastasis of cancers. However, it is uncertain whether LSD1 plays a role in facilitating colon cancer progression. Here, we have clarified the molecular mechanism by which LSD1 interacts with X-ray repair cross complementing protein 5 (Ku80) to promote colon cancer progression by directly targeting forehead protein transcription factor 2 (FOXF2). First, the interacting proteins of LSD1 were identified by immunoprecipitation and mass spectrometry. The expression of Ku80 and FOXF2 in colon cancer was detected using immunohistochemistry, real-time quantitative transcription polymerase chain reaction, and western blot. Next, the proliferation, invasion, and metastasis of colon cancer in vitro and in vivo were detected by methyl thiazolyl tetrazolium, 5-ethynyl-20-deoxyuridine, colony formation, wound healing, and nude mice xenograft model assays, respectively. Chromatin immunoprecipitation (ChIP) and ChIP-PCR were performed to investigate the molecular mechanism of LSD1 and Ku80 in colon cancer. Our results indicated that Ku80 expression was positively correlated with the invasion and migration of colon cancer cells, and negatively correlated with FOXF2 expression. More importantly, the high expression of Ku80 and the low expression of FOXF2 were particularly associated with driving the progression of colon cancer. Ku80 knockdown and LSD1 silencing inhibited the proliferation, migration, and invasion of colon cancer in vitro and in vivo. Mechanically, LSD1 interacts with Ku80 and also binds directly to the 687-887-bp portion of the FOXF2 promoter region. The upregulated methylation level of H3K4me2 in the FOXF2 promoter region facilitated the transcriptional activation of FOXF2, and downregulated protein expression associated with the Wnt/β-catenin signaling pathway. In conclusion, our study suggests that LSD1 regulates the FOXF2-mediated Wnt/β-catenin signaling pathway by interacting with Ku80, promoting the malignant biological properties of colon cancer, highlighting the binding of LSD1 and Ku80 as a useful anti-cancer target for colon cancer.