title: MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Cheng-Wu
authors.initials: CW
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Xing-Ju
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Bo-Wei
authors.initials: BW
authors.lastname: Han
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Kang-Yu
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Pan-Pan
authors.initials: PP
authors.lastname: Wei
authors.affiliation: China-America Cancer Research Institute; Key Laboratory for Medical Molecular Diagnostics of Guangdong Province; Guangdong Medical College; Dongguan, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Hematology; Medical College; Jinan University; Guangzhou, China.
authors.forename: Yangqiu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education; State Key Laboratory for Biocontrol; School of Life Science; Sun Yat-sen University; Guangzhou, China.
authors.forename: Yue-Qin
authors.initials: YQ
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D059748:Proteolysis / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C544299:DRAM2 protein, human; C531888:MIRN125 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin
keywords: PML-RARA; autophagy; degradation; leukemia; microRNA