Abstract
Objectives: MICAL-L2, a member of the molecules interacting with the CasL (MICAL) family, was reported to be highly expressed in several types of cancers, however, the roles of MICAL-L2 in NSCLC pathogenesis remain to be explored. This study is designed to clarify the mechanisms by which MICAL-L2 participates in NSCLC cell proliferation.Materials and Methods: The expression levels of MICAL-L2 in human lung cancer samples were assessed by immunohistochemical staining. Cells were transfected with siRNA or plasmids to regulate MICAL-L2 expression. Cell proliferation was measured by EdU staining and CCK-8 assays. MICAL-L2 and phosphorylated/total c-Myc expression were examined by Western blotting analysis. Interaction between MICAL-L2 and c-Myc was assessed by immunofluorescence staining, Western blotting and co-immunoprecipitation assays. Western blotting, polyubiquitylation detection and protein stability assays were used to assess whether MICAL-L2 exerts its oncogenic effect via c-Myc.Results: We found that MICAL-L2 was highly expressed in human NSCLC. While overexpressing MICAL-L2 increased NSCLC cell proliferation, MICAL-L2 depletion decreased the proliferation of NSCLC cells, an effect that was linked to cell cycle arrest. MICAL-L2 physically interacted with the c-Myc protein and functioned to maintain nuclear c-Myc levels and prolonged its half-life. Knockdown of MICAL-L2 expression led to decreased c-Myc protein stability through accelerating polyubiquitylation of c-Myc and gave rise to c-Myc degradation. We further found that MICAL-L2 deubiquitinated c-Myc and blocked its degradation, presumably by inhibiting c-Myc phosphorylation at threonine residue 58.Conclusions: These results indicate that MICAL-L2 is a key regulator of c-Myc deubiquitination and stability in the nucleus, and this activity may be involved in promoting NSCLC cell proliferation.
Highlights
Lung cancer is the most common type of malignant tumor and one of the malignancies with the fastest increase in morbidity and mortality worldwide (Torre et al, 2016)
We found that MICALL2 was highly expressed in Non-small cell lung cancer (NSCLC) tissues and cells, and its expression was associated with cell proliferation
The expression of MICAL-L2 and c-Myc was evaluated in a tissue microarray comprising 30 paired Lung adenocarcinoma (LUAD) cases
Summary
Lung cancer is the most common type of malignant tumor and one of the malignancies with the fastest increase in morbidity and mortality worldwide (Torre et al, 2016). C-Myc, an oncogene-encoded protein, is highly expressed in NSCLC and plays a key role in its carcinogenesis (Wu et al, 2015; Li et al, 2019). Understanding the mechanisms that control the level and activity of c-Myc in NSCLC is important to support the development of novel therapeutic interventions. Its expression could be influenced at the transcriptional level by c-Myc gene amplification. Protein stability is an important mechanism underlying the regulation of c-Myc protein content owing to its short half-life in proliferating cells. The degradation of c-Myc has recently been found to be regulated through a ubiquitin-independent pathway, i.e., autophagic lysosomal degradation (Liu et al, 2018; Murai et al, 2018). Whether c-Myc is deubiquitinated in the nucleus in NSCLC cells remains to be determined
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