Abstract
Circular RNAs (circRNAs) are a novel class of powerful regulators in gene expression and participate in the pathogenesis of many diseases, including cancer. However, little is known about the roles of circRNAs in the development and treatment of acute promyelocytic leukemia (APL). Here we report the expression profiling and function of circRNAs in APL, including their dynamic regulation during all-trans retinoic acid (ATRA)-induced differentiation. We performed two independent ribosomal RNA-minus RNA-sequencing (Ribo-minus RNA-seq) experiments with and without RNase R treatment on APL patient-derived NB4 cells and identified a total of 4313 circRNAs, including 1098 newly identified circRNAs. Detailed analysis showed that circRNAs expressed in APL cells were mostly exon-derived, not by-products during splicing, and could be distinguished from hematopoietic stem cells, neutrophils and lymphocytes. The true presence and stability of circRNAs were verified both in NB4 cells and primary APL patient samples. Moreover, we conducted a time-series analysis of circRNAs on ATRA-treated NB4 cells and uncovered 508 circRNAs with dynamic expression during ATRA treatment, including 246 upregulated and 262 downregulated. Further evidence demonstrated that the majority of circRNAs were regulated independently of their host linear mRNAs. Detailed functional experiments demonstrated that circ-HIPK2, one of the differentially expressed circRNAs, significantly influenced ATRA-induced differentiation of APL cells. Further mechanistic studies revealed that circ-HIPK2 was located in cytoplasm and served as a sponge for differentiation-associated miR-124-3p. Finally, circ-HIPK2 expression in APL patients was significantly lower than that in normal peripheral mononuclear cells and other subtypes of AML, indicating its potential role as an APL biomarker. Our study indicates the biological functions of circRNAs in the development and treatment of APL, and provides a comprehensive circRNA resource for future studies.
Highlights
Introduction CircularRNAs that are widely expressed in diverse cell types and species have recently emerged as a Official journal of the Cell Death Differentiation AssociationLi et al Cell Death and Disease (2018)9:651circRNAs at the genome-wide scale[2,5,6]
We found that one of the circRNAs, circ-HIPK2, significantly influenced ATRAinduced differentiation of NB4 cells, indicating that circHIPK2 was indispensable for the differentiation of acute promyelocytic leukemia (APL)
Overview of circRNA profiles used in this study To explore the molecular regulation of circRNAs in APL cells and the differentially regulated circRNAs during all-trans retinoic acid (ATRA) treatment, we performed two independent Ribominus RNA-seq, one with and one without RNase R digestion, to acquire circRNA profiles in an APL patientderived cell line NB4 before and 24 and 48 h after ATRA treatment
Summary
Introduction CircularRNAs (circRNAs) that are widely expressed in diverse cell types and species have recently emerged as a Official journal of the Cell Death Differentiation AssociationLi et al Cell Death and Disease (2018)9:651circRNAs at the genome-wide scale[2,5,6]. RNAs (circRNAs) that are widely expressed in diverse cell types and species have recently emerged as a Official journal of the Cell Death Differentiation Association. Profiling of circRNA expression has revealed that circRNAs are highly abundant in number[7], evolutionarily conserved across species[2,8], and expressed in a tissue-specific or cell typespecific manner[5,9]. These unique features indicate that circRNAs may have a biological function in various cellular processes. Several particular circRNAs have been reported to contribute to the abnormal proliferation and growth of cancer cells, such as circ-TCF25 in bladder carcinoma[19], circ-PVT1 in gastric cancer[10], and circ-001569 in colorectal cancer[20]
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