EZH2-shRNA-mediated upregulation of p21waf1/cip1 and its transcriptional enhancers with concomitant downmodulation of mutant p53 in pancreatic ductal adenocarcinoma

被引：5

作者：

Batchu, Ramesh B. ^{[1
,2
]}

Qazi, Aamer M. ^{[1
,2
]}

Gruzdyn, Oksana V. ^{[1
,2
]}

Semaan, Assaad ^{[1
,3
]}

Seward, Shelly M. ^{[1
,3
]}

Chamala, Sreedhar ^{[1
,3
]}

Dhulipala, Vasu B. ^{[1
,2
]}

Bouwman, David L. ^{[1
]}

Weaver, Donald W. ^{[1
]}

Gruber, Scott A. ^{[1
,2
]}

机构：

[1] Wayne State Univ, Lab Surg Oncol & Dev Therapeut, Dept Surg, Detroit, MI 48201 USA

[2] Wayne State Univ, John D Dingell VA Med Ctr, Detroit, MI 48201 USA

[3] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA

来源：

SURGERY | 2013年 / 154卷 / 04期

关键词：

CANCER; EZH2; EXPRESSION; GROWTH; BREAST;

D O I：

10.1016/j.surg.2013.06.041

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

Purpose. Enhancer of zeste homologue 2 (EZH2), a component of the chromatin modification protein complex, is upregulated in pancreatic ductal adenocarcinoma (PDAC), whereas loss of p53 and its downstream target, p21(waf1/cip1), is also observed frequently. We sought to investigate the role of the p53-p21(waf1/cip1) pathway in relation to EZH2-mediated inhibition of PDAC. Methods. The PANC-1 cell line was utilized in chromatin immunoprecipitation, gene profiling, Western blot, cell invasion, cell proliferation, and tumor xenograft assays. Results. Western blot analysis with antibodies that recognize both wild-type and mutant p53 did not show any alterations in band intensity; however, antibody that detects only mutant p53 showed a band of significantly lesser intensity with EZH2 knockdown. Western blot analysis further revealed a significant upregulation of p21(waf1/cip1). Gene expression profile analysis indicated significantly enhanced transcripts of transcriptional inducers of p21(waf1/cip1), with downregulation of mutant p53 transcript, corroborating the Western blot analysis. PANC-1 cells expressing EZH2-short hairpin RNA displayed markedly attenuated growth in SCID mice. Conclusion. Downregulation of mutant p53 with concomitant enhanced expression of p21(waf1/cip1) and its transcriptional trans-activators may contribute toward EZH2-mediated suppression of PDAC.

引用

页码：739 / 746

页数：8

共 20 条

[1] Curcumin Analogue CDF Inhibits Pancreatic Tumor Growth by Switching on Suppressor microRNAs and Attenuating EZH2 Expression [J].