Abstract
Cancer stem cells (CSCs) contribute to radioresistance in medulloblastoma. Thus, identification of key regulators of medulloblastoma stemness is critical for improving radiotherapy for medulloblastoma. In the present study, we profiled CSC-related long non-coding RNAs (lncRNAs) between radioresistant and parental medulloblastoma cells. The roles of the lncRNA RBM5-AS1 in the stemness and radiosensitivity of medulloblastoma cells were investigated. We found that RBM5-AS1, a novel inducer of medulloblastoma stemness, was significantly upregulated in radioresistant medulloblastoma cells compared to parental cells. Knockdown of RBM5-AS1 diminished the viability and clonogenic survival of both radioresistant and parental medulloblastoma cells after radiation. Silencing of RBM5-AS1 significantly enhanced radiation-induced apoptosis and DNA damage. In vivo studies confirmed that depletion of RBM5-AS1 inhibited tumor growth and increased radiosensitivity in a medulloblastoma xenograft model. In contrast, overexpression of RBM5-AS1 reduced radiation-induced apoptosis and DNA damage in medulloblastoma cells. Mechanistically, RBM5-AS1 interacted with and stabilized sirtuin 6 (SIRT6) protein. Silencing of SIRT6 reduced the stemness and reinforced radiation-induced DNA damage in medulloblastoma cells. Overexpression of SIRT6 rescued medulloblastoma cells from RBM5-AS1 depletion-induced radiosensitization and DNA damage. Overall, we identify RBM5-AS1 as an inducer of stemness and radioresistance in medulloblastoma. Targeting RBM5-AS1 may represent a potential strategy to overcome the resistance to radiotherapy in this malignancy.
Highlights
Medulloblastoma is one of the most common pediatric malignancies, accounting for 15–20% of all tumors of the central nervous system in children [1]
RBM5‐AS1 depletion sensitizes medulloblastoma cells to radiation treatment To identify long non-coding RNAs (lncRNAs) involved in radioresistance of medulloblastoma cells, we profiled 84 Cancer stem cells (CSCs)-related lncRNAs in radioresistant and parental DAOY cells using quantitative real-time PCR arrays
CSC-related lncRNAs were chosen given the causal relationship between cancer stemness and radioresistance [7, 8]
Summary
Medulloblastoma is one of the most common pediatric malignancies, accounting for 15–20% of all tumors of the central nervous system in children [1]. Activation of oncogenic networks including HIPPO-YAP/ TAZ and AURORA-A/MYCN pathways has been shown to promote medulloblastoma tumorigenesis and relapse [2]. Sirtuin 6 (SIRT6) belongs to the sirtuin family of protein deacetylases and participates in various biological processes, including growth, differentiation, and inflammation [11,12,13,14]. In hepatocellular carcinoma (HCC), SIRT6 can potentiate apoptosis resistance by repressing the transcription of the pro-apoptotic gene Bax [15]. SIRT6 confers resistance to DNA damage in multiple myeloma cells through downregulation of mitogenactivated protein kinase (MAPK) pathway genes [16]. Depletion of SIRT6 blocks DNA repair responses and enhances the sensitivity of acute myeloid leukemia cells to DNA-damaging agents [17].
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