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Research Paper

Regulation of autophagy by a Beclin 1-targeted microRNA, miR-30a, in cancer cells

Hua Zhu, Hao Wu, Xiuping Liu, Biao Li, Yun Chen, Xingcong Ren, Chang-Gong Liu and Jin-Ming Yang

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 nucleotides non-coding 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 other diseases.

Authors

Hua Zhu

Department of Pharmacology and The Penn State Cancer Institute; Pennsylvania State University College of Medicine; and Milton S. Hershey Medical Center; Hershey, PA USA

Hao Wu

Department of Pharmacology and The Penn State Cancer Institute; Pennsylvania State University College of Medicine; and Milton S. Hershey Medical Center; Hershey, PA USA

Xiuping Liu

Department of Experimental Therapeutics; Center for Targeted Therapy; The University of Texas-MD Anderson Cancer Center; Houston, TX USA

Biao Li

School of Informatics; Indiana University; Bloomington, Indiana USA

Yun Chen

Department of Pharmacology and The Penn State Cancer Institute; Pennsylvania State University College of Medicine; and Milton S. Hershey Medical Center; Hershey, PA USA

Xingcong Ren

Department of Pharmacology and The Penn State Cancer Institute; Pennsylvania State University College of Medicine; and Milton S. Hershey Medical Center; Hershey, PA USA

Chang-Gong Liu

Department of Experimental Therapeutics; Center for Targeted Therapy; The University of Texas-MD Anderson Cancer Center; Houston, TX USA

Jin-Ming Yang Corresponding author: juy16@psu.edu

Department of Pharmacology and The Penn State Cancer Institute; Pennsylvania State University College of Medicine; and Milton S. Hershey Medical Center; Hershey, PA USA