AP-2alpha induced epigenetic silencing of tumor suppressive genes and microsatellite instability in head and neck squamous cell carcinoma (PloS One, 2009, 4(9):e6931)

報告日期: 2010/03/12
報告時間: 17:10/18:00
報告學生: 吳長霖
講評老師: 黃溫雅
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/990312-3.pdf

AP-2a induces epigenetic silencing of tumor suppressive genes and microsatellite instability in head and neck squamous cell carcinoma

 

Kristi L. Bennett, Todd Romigh, Charis Eng

PLoS One. 2009 Sep 9;4(9):e6931

 

Speaker: Wu, Chang-Lin

Commentator: Hung, Jan-Jong, Ph.D.

Date: 2010/03/12

Place: Room 602, College of medicine

 

Abstract

Tumor suppressive genes inhibition is always found in various cancers and involved in genetic and epigenetic change. In eukaryotic cell, AP-2 family (a, b, γ, ε, δ) plays roles in apoptosis, cell cycle regulation, tissue differentiation, and development. AP-2a, one of AP-2 family members, has been known to correlate with progression in various squamous cell carcinomas, and recently was found to over express in ~70% HNSCC patient samples. Moreover, AP-2a has been shown to recruit HDACs to specific gene promoters, and was found that regions of frequent methylation often contained AP-2a binding site in acute lymphoblastic leukemia. In this study, the authors aimed to identify if activator protein-2 alpha (AP-2a) is associated with HNSCC pathogenesis. They suggested that AP-2a may bind to specific target genes, silence transcription, and propagate DNA methylation in order to stably silence tumor suppressors and DNA repair genes. Stable down regulation of AP-2a by shRNA in HNSCC cell line not only decreased the methylation level of its target genes, but also increased target gene expression level. Furthermore, AP-2a down regulated by shRNA decreased MLH1 methylation level in HNSCC cell lines revealed DNA microsatellite instability. Through chromatin immune-precipitation (ChIP) analysis, the authors confirm that AP-2a is required for HDAC1/2 recruitment, and by the effect of HDAC inhibition on target methylation may explain how AP-2a plays a role in methylation. In conclusion, AP-2a plays a role not only in epigenetic silencing, but also in genomic instability. Interestedly, the novel discovery is AP-2a appears to contribute to microsatellite instability in HNSCC.

 

References

1. Damberg M (2005) Transcription factor AP-2 and monoaminergic functions in the central nervous system. J Neural Transm 112: 1281–1296.

2. Bennett KL, Romigh T, Arab K, Teresi RE, Tada Y, et al. (2009) Activator protein 2 alpha (AP2alpha) suppresses 42 kDa C/CAAT enhancer binding protein alpha (p42(C/EBPalpha)) in head and neck squamous cell carcinoma. Int J Cancer 124: 1285–1292.