A DNA Methylation-Dependent NOP56/MYC Positive Feedback Loop Promotes the Proliferation and Migration of Non-Small Cell Lung Cancer Through Regulating Ribosome Biogenesis.

Background: Recent findings underscore the importance of ribosome biogenesis, a complex molecular machinery, in cancer biology, highlighting opportunities for targeted treatment strategies. Here, we revealed that dysregulation of ribosome biogenesis is a distinctive feature of non-small lung cancer (NSCLC). However, further investigation is required to pinpoint which specific processes within this complex pathway are aberrant in this malignancy. Methods: The expression levels and clinical significance of NOP56 in NSCLC were investigated by microarray analysis, qPCR, TCGA and GEO datasets. Function assays were conducted to explore the biological role of NOP56 in NSCLC cells. The mechanisms that mediate the upregulation of NOP56 were investigated by bisulfite DNA sequencing, luciferase reporter assay, chromatin immunoprecipitation and TCGA datasets. The downstream pathway of NOP56 was explored by RNA sequencing, qPCR, Western blot and luciferase reporter assay. Results: High expression of NOP56 was detected in NSCLC tissues and was associated with poor prognosis. Functional assays revealed that overexpression of NOP56 promoted NSCLC cellular proliferation, metastasis and ribosome biogenesis in vitro, and further accelerated tumorigenesis in vivo. Mechanistically, NOP56 activates MYC signaling by regulating IRES-dependent translation, which in turn transcriptionally upregulated NOP56 expression, creating a positive feedback loop. Additionally, hypomethylation also contributed to the upregulation of NOP56 in NSCLC. Conclusions: Our study demonstrated that NOP56/MYC forms a positive feedback loop that enhances ribosome biogenesis and drives the progression of NSLSC, positioning NOP56 a promising therapeutic target for this malignancy.