Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells.
beclin 1, the mammalian homologue of the yeast Atg6, is a key autophagy-promoting gene that plays a critical role in the regulation of cell death and survival of various types of cells. However, recent studies have observed that the expression of beclin 1 is altered in certain diseases including cancers. The causes underlying the aberrant expression of beclin 1 remain largely unknown. We report here that microRNAs (miRNAs), a class of endogenous, 22-24 nucleotide noncoding RNA molecules able to affect stability and translation of mRNA, may represent a previously unrecognized mechanism for regulating beclin 1 expression and autophagy. We demonstrated that beclin 1 is a potential target for miRNA miR-30a, and this miRNA could negatively regulate beclin 1 expression resulting in decreased autophagic activity. Treatment of tumor cells with the miR-30a mimic decreased, and with the antagomir increased, the expression of beclin 1 mRNA and protein. Dual luciferase reporter assay confirmed that the miR-30a binding sequences in the 3'-UTR of beclin 1 contribute to the modulation of beclin 1 expression by miR-30a. Furthermore, inhibition of beclin 1 expression by the miR-30a mimic blunted activation of autophagy induced by rapamycin. Our study of the role of miR-30a in regulating beclin 1 expression and autophagy reveals a novel function for miRNA in a critical cellular event with significant impacts in cancer development, progression and treatment, and in other diseases.
Zhu
Hua
H
Department of Pharmacology and The Penn State Cancer Institute, Pennsylvania State University College of Medicine, and Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA.
Wu
Hao
H
Liu
Xiuping
X
Li
Biao
B
Chen
Yun
Y
Ren
Xingcong
X
Liu
Chang-Gong
CG
Yang
Jin-Ming
JM
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D001483:Base Sequence; D000071186:Beclin-1; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D000077185:Resveratrol; D020123:Sirolimus / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C546086:MIRN30b microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D013267:Stilbenes; D000077185:Resveratrol; D020123:Sirolimus