Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER

被引：187

作者：

van den Beucken, Twan ^{[1
,2
,3
,4
]}

Koch, Elizabeth ^{[1
,2
,5
]}

Chu, Kenneth ^{[6
]}

Rupaimoole, Rajesha ^{[7
,8
]}

Prickaerts, Peggy ^{[9
]}

Adriaens, Michiel ^{[10
,11
]}

Voncken, Jan Willem ^{[9
]}

Harris, Adrian L. ^{[12
]}

Buffa, Francesca M. ^{[12
]}

Haider, Syed

Starmans, Maud H. W. ^{[3
,6
]}

Yao, Cindy Q. ^{[5
,6
]}

Ivan, Mircea

Ivan, Cristina ^{[13
,14
]}

Pecot, Chad V. ^{[15
]}

Boutros, Paul C. ^{[5
,6
,16
]}

Sood, Anil K. ^{[14
]}

Koritzinsky, Marianne ^{[1
,2
,17
,18
]}

Wouters, Bradly G. ^{[1
,2
,3
,5
,18
,19
]}

机构：

[1] Princess Margaret Canc Ctr, Toronto, ON M5G IL7, Canada

[2] Campbell Family Inst Canc Res, Univ Hlth Network, Toronto, ON M5G IL7, Canada

[3] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Radiat Oncol, NL-6200 MD Maastricht, Netherlands

[4] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Toxicogen, NL-6200 MD Maastricht, Netherlands

[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[6] Ontario Inst Canc Res, Informat & Biocomp Program, Toronto, ON M5G 1L7, Canada

[7] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[9] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands

[10] Maastricht Univ, BiGCaT, Dept Bioinformat, NL-6200 MD Maastricht, Netherlands

[11] Maastricht Univ, BiGCaT, Dept Bioinformat, NL-6200 MD Maastricht, Netherlands

[12] John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK Dept Oncol, Oxford OX3 9DS, England

[13] Indiana Univ, Melvin & Bren Simon Canc Ctr, Dept Med, Indianapolis, IN 46202 USA

[14] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Non Coding RNAs, Houston, TX 77030 USA

[15] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Oncol, Houston, TX 77030 USA

[16] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[17] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada

[18] Univ Toronto, Dept Radiat Oncol, Toronto, ON M5T 1P5, Canada

[19] Ontario Inst Canc Res, Select Therapies Program, Toronto, ON M5G 1L7, Canada

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; DEMETHYLASE JMJD3 CONTRIBUTES; SOMATIC MUTATIONS; INDUCIBLE FACTORS; DOWN-REGULATION; CANCER CELLS; EXPRESSION; EZH2; METASTASIS; MICRORNAS;

D O I：

10.1038/ncomms6203

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

MicroRNAs are small regulatory RNAs that post transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet, the underlying mechanisms are not well understood. Here we identify tumour hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumour stem cell phenotypes that may underlie poor outcome in breast cancer.

引用

页数：13

共 71 条

[1] The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence [J].