Hypoxia-induced long non-coding RNA DARS-AS1 regulates RBM39 stability to promote myeloma malignancy
Jia Tong,
Xiaoguang Xu,
Zilu Zhang,
Chengning Ma,
Rufang Xiang,
Jia Liu,
Wenbin Xu,
Chao Wu,
Junmin Li,
Fenghuang Zhan,
Yingli Wu,
Hua Yan
Affiliations
Jia Tong
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Xiaoguang Xu
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zilu Zhang
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Chengning Ma
Hongqiao 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
Rufang Xiang
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jia Liu
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wenbin Xu
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Chao Wu
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Junmin Li
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China
Fenghuang Zhan
Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
Yingli Wu
Hongqiao 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
Hua Yan
Department of Hematology, Affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China;Department of General Practice, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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 overexpression. We reveal that a novel HIF-1/DARS-AS1/RBM39 pathway is implicated in the pathogenesis of myeloma. Targeting DARS-AS1/RBM39 may, therefore, represent a novel strategy to combat myeloma.
