An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development

Background SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. Methods The expression of SETD1A, NEAT1, EZH2, and beta-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models. Results SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/beta-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/beta-catenin pathway via interacting with and stabilizing beta-catenin. The SET domain is dispensable for the interaction between SETD1A and beta-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/beta-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/beta-catenin pathway, thus forming a positive feedback loop in NSCLC cells. Conclusion SETD1A and Wnt/beta-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.

Automated summary

SETD1A is significantly upregulated in NSCLC, and its overexpression predicts a poor prognosis for patients. Functional experiments demonstrate that SETD1A positively regulates cancer stem cell properties and negatively regulates cisplatin sensitivity in NSCLC cells through the Wnt/beta-catenin pathway. Additionally, SETD1A interacts with and stabilizes beta-catenin to positively regulate the Wnt/beta-catenin pathway.