Lung cancer is the leading cause of cancer-related death worldwide, underscoring the importance of understanding the molecular mechanisms responsible of lung cancer initiation, progression and metastasis. One major characteristic and important diagnostic criterion for lung cancer and other neoplasias is the aberrant nuclear structure. The nuclear lamins, which are the structural component of nuclear envelope, has been shown to be critical determinants of nuclear structure, shape and genome integrity. In the present study, we demonstrate a critical role of lamin B1 loss in facilitating lung cancer development, migration and metastasis. First, we observed significant lower levels of lamin B1 in human lung cancer tissues in comparison with normal lung tissues. Furthermore, lamin B1 haploinsufficiency is sufficient to induce spontaneous pulmonary tumor formation in mice model, suggesting that loss of lamin B1 promotes lung cancer initiation. Moreover, lamin B1 depletion triggers epithelial-mesenchymal transition (EMT) and facilitates cancer cell migration and metastasis via upregulating the receptor tyrosine kinase RET. RET upregulation upon lamin B1 silencing further activates p38 signaling pathway. Targeting both RET and its downstream target p38 repressed lamin B1 depletion mediated cancer cell migration and metastasis. Consistently, lamin B1 and RET expressions show inverse correlation in lung cancer patients.Mechanistically, we show that loss of lamin B1 results in global decrease in H3K27me3 and reduces the occupancy of H3K27me3 at Ret promoter by disrupting the recruitment of methyltransferase EZH1 and EZH2 to the chromatin and Ret promoter, thus leading to the transcriptional activation of Ret gene. Taken together, our data demonstrate a role of lamin B1 as a tumor suppressor in lung cancer by epigenetically repressing the RET expression, prospecting a novel therapeutic strategy by targeting RET in the treatment of lung cancer patients with lamin B1 loss.
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