Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer.
Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancer cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). We propose that the genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.
Varambally
Sooryanarayana
S
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cao
Qi
Q
Mani
Ram-Shankar
RS
Shankar
Sunita
S
Wang
Xiaosong
X
Ateeq
Bushra
B
Laxman
Bharathi
B
Cao
Xuhong
X
Jing
Xiaojun
X
Ramnarayanan
Kalpana
K
Brenner
J Chad
JC
Yu
Jindan
J
Kim
Jung H
JH
Han
Bo
B
Tan
Patrick
P
Kumar-Sinha
Chandan
C
Lonigro
Robert J
RJ
Palanisamy
Nallasivam
N
Maher
Christopher A
CA
Chinnaiyan
Arul M
AM
D020413:3' Untranslated Regions; D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D006657:Histones; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine