Research from Ming Shi and Shan Wang showed the biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer.
In this study, they reported the correlation between MARVELD1 silencing and lung cancer. Immunohistochemical analysis and Western blotting experiments showed that the down-regulation of MARVELD1 was associated with malignant progression of lung cancer. Epigenetic silencing of MARVELD1 gene was observed in low MARVELD1-expressing lung cancer cell lines. Therefore, they deducted that MARVELD1 silencing may be required for tumorigenesis and has a potential to be developed as a biomarker for malignant phenotype of lung cancer, which possesses considerable value in prognosis prediction, progression monitoring and treatment evaluating. For future application, it is critical to design reasonable clinical trial for evaluation of this biomarker. Not only Overall survival (OS) and Disease-free survival (DFS) should be evaluated in randomized, controlled trials, some key factors with regard to lung cancer, such as smoking history information, will be considered.
Hypermethylation of tumor suppressor genes and demethylation of oncogenes contribute to tumorigenesis. Cancer-linked hypermethylation and hypomethylation of gene promoter is often associated with cell proliferation. MARVELD1 is a potential tumor suppressor, which negatively regulates proliferation of cancer cells. In this study, they observed that MARVELD1 is down-regulated in lung cancer tissues, especially small-cell lung cancer tissues. In lung cancer cell lines, the methylation states of the CpGs in MARVELD1 promoter region were found to be hypermethylated. Moreover, MARVELD1 gene was also re-expressed following treatment with 5-aza-CdR, a potent demethylating agent, suggesting that status of DNA demethylation was important for the active expression of MARVELD1. In addition, we also found histone acetylation and DNA demethylation synergistically activated MARVELD1 gene in lung cancer cells.
Previous results showed that MARVELD1 could suppress cell spreading and actin organization through regulation of pre-mRNA processing, a process parallel to NMD. Moreover, MARVELD1 associated with potential NMD factor Importin β1, suggesting the possible function of MARVELD1 in NMD pathway. A recent study further showed that MARVELD1 regulated NMD via modulating phosphorylation of UPF1. Considering the aberrant regulation of MARVELD1 gene in lung cancer, therefore, they discussed the gene silencing mechanism of MARVELD1 and the relationship between epigenetically masked MARVELD1 and NMD function in lung cancer cells.
Although NMD pathway has been extensively studied, the regulatory mechanism of NMD in cancer is still not well understood. In this study, they showed MARVELD1 co-localized and interacted with SMG1, the core kinase of the NMD machinery, in lung cancer cells. Moreover, they constructed the NMD reporter plasmid expressing PTC-containing truncated LRP1B-GFP mRNA (LRP1B exons 1–9 from lung cancer cell line QG56), and demonstrated that MARVELD1 bound PTC-mRNA as efficient as NMD core factor UPF1 and SMG1 by RNA-ChIP based reporter system. In addition, they also found MARVELD1 could enhance the association between NMD complex UPF1/SMG1 and PTC-containing mRNA, which suggested that MARVELD1 was involved in modulating the efficiency of NMD through interaction with SMG1. In summary, their study suggested the following working model(Figure1). The reduced MARVELD1 expression, due to promoter hypermethylation, attenuated NMD, which indicated aberrant mRNA surveillance mechanism in lung cancer.
Reference
Ming Shi, Shan Wang and Yuanfei Yao,etc., Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer, Scientific Reports 4, Article number: 7545︱doi:10.1038/srep07545