Hypermethylation of BEND5 contributes to cell proliferation and is a prognostic marker of colorectal cancer

• Published in: Oncotarget Vol. 8; no. 69; pp. 113431 - 113443
• Main Authors: Lin, Ruo-Kai, Hung, Wan-Yu, Huang, Yu-Fang, Chang, Yu-Jia, Lin, Chien-Hsing, Chen, Wei-Yu, Chiu, Shih-Feng, Chang, Shih-Ching, Tsai, Shih-Feng
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 26.12.2017
• Subjects: Research Paper; DNA methylation; prognostic marker; tumor suppressor genes; colorectal cancer; BEND5
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.22266

Aberrant hypermethylation of CpG islands in tumor suppressor genes (TSGs) contributes to colorectal tumorigenesis. To identify new colorectal cancer (CRC) screening marker, we investigated DNA methylation alterations in novel TSGs. Using HumanMethylation450 BeadChip arrays, CpG regions in were the most highly methylated among all genomic regions in 26 colorectal tumors compared to paired non-neoplastic tissues from a Taiwan cohort. Therefore, was selected for further analysis. Quantitative methylation-specific real-time PCR revealed that 86.7% (117/135) of CRC patients exhibited hypermethylated . Real-time reverse transcription PCR identified that BEND5 mRNA expression was downregulated in 68% (32/47) of the analyzed samples. hypermethylation was associated with poor overall survival (OS) in Taiwan patients with early-stage CRC ( 0.037). In a CRC tissue set from South Korea, OS was higher in patients with high BEND5 protein expression than in those with low BEND5 protein expression ( 0.037) by using immunohistochemistry assays. Consistently, BEND5 hypermethylation was associated with poor OS in patients with early-stage CRC in The Cancer Genome Atlas (TCGA) data set ( 0.003). Multivariate Cox proportional hazards regression analysis further supported that hypermethylation of BEND5 genes was significantly associated with OS in Taiwan and TCGA CRC patients ( 0.023 and 0.033, respectively). Finally, the cell model assay with transient transfection of BEND5 or si-BEND5 knockdown indicated that BEND5 inhibited cancer cell proliferation. In conclusion, epigenetic alteration in the candidate TSG contributes to colorectal cancer development and is a prognostic marker of CRC.