title: Aberrant upregulation of ASCL2 by promoter demethylation promotes the growth and resistance to 5-fluorouracil of gastric cancer cells.
abstract: Achaete scute-like 2 (ASCL2), a basic helix-loop-helix transcription factor, plays an essential role in the maintenance of adult intestinal stem cells. However, the function of ASCL2 in gastric cancer (GC) is poorly understood. Therefore, we investigated the roles and regulatory transcription mechanisms of ASCL2 in GC. Gene expression and methylation data analysis showed that ASCL2 was upregulated and hypomethylated in GC tissues. Using real-time RT-PCR and pyrosequencing analysis, we confirmed that ASCL2 was overexpressed and hypomethylated in GC tissues compared to adjacent normal tissues. We then investigated the mechanisms underlying the aberrant expression of ASCL2 in GC and found that treatment with a methylation inhibitor induced ASCL2 expression in GC cell lines. MBD-sequencing assay also revealed hypermethylation of the promoter region of ASCL2 in GC cell lines, which barely expressed the ASCL2 gene. Furthermore, ASCL2 expression levels were inversely correlated with GC patient survival. Ectopic overexpression of ASCL2 showed that ASCL2 increased cell growth and promoted resistance to 5-fluorouracil in GC cells. These results suggest that ASCL2 might play an important role in gastric tumor growth and chemoresistance, and could be a useful prognostic marker for GC patients.
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Oh-Hyung
authors.initials: OH
authors.lastname: Kwon
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Park
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Baek
authors.forename: Seung-Moo
authors.initials: SM
authors.lastname: Noh
authors.forename: Kyu-Sang
authors.initials: KS
authors.lastname: Song
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005472:Fluorouracil; C065501:ASCL2 protein, human