RNA demethylase ALKBH5 promotes tumorigenesis in multiple myeloma via TRAF1-mediated activation of NF-κB and MAPK signaling pathways

• Published in: Oncogene 2022-01, Vol.41 (3), p.400-413
• Main Authors: Qu, Jianwei, Hou, Yifan, Chen, Qingxiao, Chen, Jing, Li, Yi, Zhang, Enfan, Gu, Huiyao, Xu, Ruyi, Liu, Yang, Cao, Wen, Zhang, Jinna, Cao, Liqin, He, Jingsong, Cai, Zhen
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/95; 3' Untranslated regions; 38/39; 38/61; 38/77; 38/90; 38/91; 631/67/1990/804; 631/67/395; 692/53/2422; AlkB Homolog 5, RNA Demethylase - metabolism; Apoptosis; Carcinogenesis; Cell Biology; Cell culture; Cell Line, Tumor; Cell Proliferation; Cell survival; Gene expression; Gene set enrichment analysis; Human Genetics; Humans; Internal Medicine; MAP kinase; MAP Kinase Signaling System - genetics; Medical prognosis; Medicine; Medicine & Public Health; mRNA stability; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - mortality; Multiple Myeloma - pathology; N6-methyladenosine; NF-kappa B - metabolism; NF-κB protein; Oncology; Prognosis; RNA modification; Signal transduction; Survival Analysis; Therapeutic targets; TNF Receptor-Associated Factor 1 - metabolism; Transcriptomes; Tumor necrosis factor; Tumor necrosis factor receptors; Tumorigenesis; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-02095-8

N 6 -methyladenosine (m 6 A), an internal modification in mRNA, plays a critical role in regulating gene expression. Dysregulation of m 6 A modifiers promotes oncogenesis through enzymatic functions that disrupt the balance between the deposition and removal of m 6 A modification on critical transcripts. However, the roles of mRNA m 6 A in multiple myeloma (MM) are poorly understood. The present study showed that RNA demethylase ALKBH5 was overexpressed in MM and associated with a poor prognosis in MM patients. Knocking down ALKBH5 induced apoptosis and inhibited the growth of MM cells in vitro. Xenograft models and gene set enrichment analysis with patient transcriptome datasets also supported the oncogenic role of ALKBH5 in MM. Mechanistic studies showed that ALKBH5 exerted tumorigenic effects in myeloma in an m 6 A-dependent manner, and TNF receptor-associated factor 1 (TRAF1) was a critical target of ALKBH5. Specifically, ALKBH5 regulated TRAF1 expression via decreasing m 6 A abundance in the 3'-untranslated region (3'-UTR) of TRAF1 transcripts and enhancing TRAF1 mRNA stability. As a result, ALKBH5 promoted MM cell growth and survival through TRAF1-mediated activation of NF-κB and MAPK signaling pathways. Collectively, our data demonstrated that ALKBH5 played a critical role in MM tumorigenesis and suggested that ALKBH5 could be a novel therapeutic target in MM.