Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells.
Estrogen receptor α (ERα) upregulation causes abnormal cell proliferation in about two thirds of breast cancers, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high expression of the microRNA miR-375 in ERα-positive breast cell lines is a key driver of their proliferation. miR-375 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypomethylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ERα with regulatory regions of miR-375. Inhibiting miR-375 in ERα-positive MCF-7 cells resulted in reduced ERα activation and cell proliferation. A combination of expression profiling from tumor samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigations revealed that miR-375 regulates RASD1 by targeting the 3' untranslated region in RASD1 mRNA. Additionally, we found that RASD1 negatively regulates ERα expression. Our findings define a forward feedback pathway in control of ERα expression, highlighting new strategies to treat ERα-positive invasive breast tumors.
Division of Functional Genome Analysis, Helmholtz-University-Young Investigator Group Molecular RNA Biology and Cancer, German Cancer Research Center (DKFZ) & Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Pedro
P
de Souza Rocha Simonini
Achim
A
Breiling
Nibedita
N
Gupta
Mahdi
M
Malekpour
Mahmoud
M
Youns
Ramesh
R
Omranipour
Fatemeh
F
Malekpour
Stefano
S
Volinia
Carlo M
CM
Croce
Hossein
H
Najmabadi
Sven
S
Diederichs
Ozgür
O
Sahin
Doris
D
Mayer
Frank
F
Lyko
Jörg D
JD
Hoheisel
Yasser
Y
Riazalhosseini
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000076246:CCCTC-Binding Factor; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006657:Histones; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; C400132:RASD1 protein, human; D012097:Repressor Proteins; D018631:ras Proteins; D008239:Lysine