Aberrant methylation in promoter regions of cyclin‐dependent kinase inhibitor genes in adenoid cystic carcinoma of the salivary gland

Abstract

Adenoid cystic carcinoma (ACC) is a common malignant neoplasm of the salivary gland. The mechanism underlying ACC carcinogenesis is not fully elucidated, although data on associated genetic alterations are accumulating. Cyclin-dependent kinase inhibitors (CKIs) act as tumor suppressors in various cancers, and aberrant methylation in the CKI gene promoter region has been linked to gene silencing and downregulation of expression. The present study investigated methylation of CKI genes, p15, p18, p19, p21, and p27, in 34 cases of ACC. We found frequent and plural methylations of these genes in most cases (68.8% in p15, 90.3% in p18, 78.8% in p19, 92.3% in p21, and 26.5% in p27). Cell cycle disruption induced by these epigenetic aberrations might be important in the tumorigenesis of ACC.

LncRNA SNHG6 is Associated with Poor Prognosis of Gastric Cancer and Promotes Cell Proliferation and EMT through Epigenetically Silencing p27 and Sponging miR-101-3p

“…CKIs, as tumor suppressors, are responsible for the modulation of the activity of Cdk/cyclin complexes [35]. And the aberrant methylation such as PRC2-mediated histone methylation in the CKI gene promoter region is associated with gene expression suppression [36-39]. Additionally, plenty of lncRNAs have been reported to modulate specific genetic loci through recruiting PRC2 and PRC2-mediated epigenetic regulation play important role in tumorigenesis [17, 30, 31, 40-42].…”

Molecular biology of adenoid cystic carcinoma

“…14-3-3 σ negatively regulates the cell cycle by binding to cyclin/CDK complexes and inhibiting their interactions, thereby preventing cell cycle progression (124) . It has been shown to be required for stable G2 cell cycle arrest and also for activating p53 after DNA damage (125) . 14-3-3 σ is silenced via promoter methylation in many types of tumors (125) .…”

“…It has been shown to be required for stable G2 cell cycle arrest and also for activating p53 after DNA damage (125) . 14-3-3 σ is silenced via promoter methylation in many types of tumors (125) . In ACC Uchida et al (118) reported promoter methylation of 14-3-3 σ in 8 out of 14 tumors and demonstrated that the aberrant methylation was in fact responsible for decreased gene expression.…”

“…One particular member of the CKI family, P27 , has been shown to be a prognostic marker for human cancers. Daa et al (125) analyzed promoter methylation of this and other CKI genes including p15 , p18 , p19 , and p21 in 34 cases of ACCs by MSP. The incidences of promoter methylation in ACC tumors were 68.8% for p15 , 90.3% for p18 , 7.8% for p19 , 92.3% for p21 , and 26.5% for p27 .…”

Suprabasin Is Hypomethylated and Associated with Metastasis in Salivary Adenoid Cystic Carcinoma

“…These methylation changes can result in aberrant activation of oncogenes (by hypomethylation) or silencing of tumor suppressor genes (by hypermethylation). Several methylation-regulated, ACC-associated candidate genes have been identified, including PTEN [4], cyclin-dependent kinase inhibitors [5], RASSF1 , RARbeta2 [6] p16 INK4a , DAPK [7], 14-3-3 sigma [8], E-cadherin [9], and AQP1 [10]. Since DNA methylation and transcription regulation are frequent events in human cancers, our group has developed epigenomic screening methods to search for novel hypomethylated oncogene candidates in various types of human cancers, including salivary gland ACC [10].…”