Myofibrillogenesis Regulator‐1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin‐Protein Ligase Itchy Homolog in the Metastasis of Non‐Small Cell Lung Cancer

Abstract Myofibrillogenesis regulator‐1 (MR‐1) is a multifunctional protein involved in the development of various human tumors. The study is the first to report the promoting effect of MR‐1 on the development and metastasis of non‐small cell lung cancer (NSCLC). MR‐1 is upregulated in NSCLC and positively associated with poor prognosis. The overexpression of MR‐1 promotes the metastasis of NSCLC cells by stabilizing the expression of Notch3‐ICD (NICD3) in the cytoplasm through enrichment analysis, in vitro and in vivo experimental researches. And Notch3 signaling can upregulate many genes related to metastasis. The stabilizing effect of MR‐1 on NICD3 is achieved through the mono‐ubiquitin lysosomal pathway and the specific E3 ubiquitin ligase is Itchy homolog (ITCH). There is a certain interaction between MR‐1 and NICD3. Elevated MR‐1 can affect the level of ITCH phosphorylation, reduce its E3 enzyme activity, and thus lead to reduce the ubiquitination and degradation of NICD3. Interference with the interaction between MR‐1 and NICD3 can increase the degradation of NICD3 and impair the metastatic ability of NSCLC cells, which is a previously overlooked treatment option in NSCLC. In summary, interference with the interaction between MR‐1 and NICD3 in the progression of lung cancer may be a promising therapeutic target.