Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target.

Chin-Sheng Hung,Tzong-Huei Lee,Sheng-Chao Wang,Yi-Ting Yen,Ruo-Kai Lin,Wu-Che Wen

doi:10.3390/ijms19103096

Abstract

Lung and breast cancer are the leading causes of mortality in women worldwide. The discovery of molecular alterations that underlie these two cancers and corresponding drugs has contributed to precision medicine. We found that CCND2 is a common target in lung and breast cancer. Hypermethylation of the CCND2 gene was reported previously; however, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery. Genome-wide methylation and quantitative methylation-specific real-time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients. As compared with paired normal tissues and healthy individuals, CCND2 promoter hypermethylation was detected in 40.9% of breast tumors and 44.4% of plasma circulating cell-free DNA of patients. The western cohort of The Cancer Genome Atlas also demonstrated CCND2 promoter hypermethylation in female lung cancer, lung adenocarcinoma, and breast cancer patients and that CCND2 promoter hypermethylation is an independent poor prognostic factor. The cell model assay indicated that CCND2 expression inhibited cancer cell growth and migration ability. The demethylating agent antroquinonol D upregulated CCND2 expression, caused cell cycle arrest, and inhibited cancer cell growth and migration ability. In conclusion, hypermethylation of CCND2 is a potential diagnostic, prognostic marker and drug target, and it is induced by antroquinonol D.

Highlights

Lung cancer and breast cancer are the most common and leading causes of mortality in women worldwide [1,2]
Promoter hypermethylation of CCND2 and low CCND2 expression were associated with a poor prognosis, especially in non-small cell lung cancer (NSCLC) and breast cancer patients
We found that antroquinonol D, which is a demethylating agent and an analog of the fungal-derived Taiwanese natural product antroquinonol, could induce CCND2 mRNA and protein expression, cell cycle arrest, and migration inhibition in lung and breast cancer cell lines

Summary

Introduction

Lung cancer and breast cancer are the most common and leading causes of mortality in women worldwide [1,2]. A novel diagnostic biomarker and candidate treatment target specific for lung adenocarcinoma and TNBC was investigated in this study. Hypermethylation of the CCND2 gene is common in many cancers, including lung and breast cancer, and it results in low CCND2 expression [12,13,14,15]. CCND2 hypermethylation, and, low CCND2 protein expression are associated with a poor prognosis in epithelial ovarian cell cancer [17] and hepatocellular carcinoma recurrence [18]. We found that low CCND2 expression was associated with a poor prognosis, especially in patients with non-small cell lung cancer (NSCLC) or breast cancer; CCND2 might serve as a potential drug target. We investigated whether CCND2 is a potential drug target and it is identified a CCND2 inducer drug

Methods

Results

Conclusion