Inactivation of ADAMTS18 by aberrant promoter hypermethylation contribute to lung cancer progression

Published Nov 13, 2018Journal of cellular physiology

How Turning Off ADAMTS18 by Abnormal DNA Methylation May Help Lung Cancer Grow

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Abstract

ADAMTS18 expression is silenced in lung cancer cells due to promoter methylation.

Promoter methylation frequently occurs in ADAMTS18 in lung tumors compared to normal lung tissue.
Restoration of ADAMTS18 expression can be achieved through demethylation treatments.
Overexpression of ADAMTS18 in lung cancer cells leads to reduced cell proliferation, migration, and invasiveness.
ADAMTS18 induces G0/G1 cell cycle arrest in lung cancer cells.
The suppression of EGFR/AKT signaling by ADAMTS18 enhances lung cancer cell sensitivity to cisplatin.
ADAMTS18 promoter methylation may serve as a potential epigenetic biomarker for early detection of lung cancer.

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Lung cancer is the most frequently diagnosed cancer worldwide. Epigenetic regulation contributes to lung cancer pathogenesis. The ADAMTS18 tumor suppressor gene is inactivated in some cancers, but its involvement in lung cancer has not been shown. Immunohistochemistry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and methylation-specific PCR were used to assay ADAMTS18 expression and promoter methylation in lung tumor tissues and adjacent tissues. Cell viability, transwell, and wound-healing assays, as well as flow cytometry were used to characterize the biological activity of ADAMTS18. The influence of ADAMTS18 on protein expression was assayed using western blots analysis, and its effect on chemosensitivity was assayed by the response to cisplatin. We found that ADAMTS18 was silenced in lung cancer cells by promoter methylation. Demethylation by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine, with or without the histone deacetylase inhibitor trichostatin A, restored ADAMTS18 expression. Compared with normal lung tissue, ADAMTS18 in lung tumors was frequently methylated. Overexpression of ADAMTS18 in lung cancer cells inhibited cell proliferation, migration, and invasiveness and induced G0/G1 cell cycle arrest. Furthermore, ADAMTS18 suppressed epidermal growth factor receptor/protein kinase B (EGFR/AKT) signaling, which sensitized lung cancer cells to cisplatin. Thus, our results demonstrated that the tumor suppressor gene ADAMTS18 was downregulated in lung cancer by promoter CpG methylation, and it promoted sensitivity to cisplatin via EGFR/AKT signaling. Our study suggests that ADAMTS18 promoter methylation is a potential epigenetic biomarker for early detection of lung cancer and warrants investigation as a therapeutic target for early-stage lung cancer.

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Inactivation of ADAMTS18 by aberrant promoter hypermethylation contribute to lung cancer progression

Abstract

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