Page 172 - Haematologica - Vol. 105 n. 6 - June 2020

Plasma Cell Disorders
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1630-1640
Hypoxia-induced long non-coding RNA DARS-AS1 regulates RBM39 stability to promote myeloma malignancy
Jia Tong,1,* Xiaoguang Xu,1,* Zilu Zhang,1 Chengning Ma,2 Rufang Xiang,1 Jia Liu,1 Wenbin Xu,1 Chao Wu,1 Junmin Li,1 Fenghuang Zhan,3 Yingli Wu2 and Hua Yan1,4
1Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA and 4Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
*JA and XX contributed equally as co-first authors.
ABSTRACT
Multiple myeloma is a malignant plasma-cell disease, which is highly dependent on the hypoxic bone marrow microenvironment. However, the underlying mechanisms of hypoxia contributing to myeloma genesis are not fully understood. Here, we show that long non- coding RNA DARS-AS1 in myeloma is directly upregulated by hypoxia inducible factor (HIF)-1. Importantly, DARS-AS1 is required for the survival and tumorigenesis of myeloma cells both in vitro and in vivo. DARS-AS1 exerts its function by binding RNA-binding motif protein 39 (RBM39), which impedes the interaction between RBM39 and its E3 ubiquitin ligase RNF147, and prevents RBM39 from degradation. The overexpression of RBM39 observed in myeloma cells is associated with poor prognosis. Furthermore, knockdown of DARS-AS1 inhibits the mammalian target of rapamycin signaling pathway, an effect that is reversed by RBM39 overex- pression. We reveal that a novel HIF-1/DARS-AS1/RBM39 pathway is impli- cated in the pathogenesis of myeloma. Targeting DARS-AS1/RBM39 may, therefore, represent a novel strategy to combat myeloma.
Introduction
Multiple myeloma (MM) is characterized by abnormal accumulation of mono- clonal plasma cells in the bone marrow and broad clinical and pathophysiological heterogeneity leading to a fatal outcome. Hypoxia in specific bone marrow niches induces numerous changes in the expression of genes that contribute to the main- tenance of myeloma cells and the progression of myeloma, leading to drug resist- ance and cancer recurrence.1 Focusing on the hypoxia-related pathogenic mecha- nisms in myeloma may facilitate the optimization of the choice of therapeutic reg- imen and improve clinical outcomes.
Long non-coding RNA (lncRNA) are mRNA-like transcripts that are longer than 200 nucleotides.2,3 Accumulating evidence indicates that lncRNA are crucial mole- cules that participate in gene regulation at the epigenetic, transcriptional, and post- transcriptional levels.3,4 Aberrant expression of lncRNA can promote the development and progression of malignant tumors through contributing to proliferation, invasion and metastasis.5-7 lncRNA may, therefoe, serve as potential diagnostic biomarkers and therapeutic targets for cancers. However, few lncRNA have been functionally studied in MM. Many hypoxia inducible factor (HIF)-dependent protein-coding genes con- tribute to adaptation to hypoxia. Whether lncRNA are involved in the response to hypoxia in myeloma and the determination of their regulatory roles is important for a better understanding of the development and progression of myeloma.
Correspondence:
HUA YAN
yanhua_candy@163.com
YINGLI WU
wuyingli@shsmu.edu.cn
Received: February 1, 2019. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2019.218289
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1630
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