Abstract
Osteosarcoma (OS) is a primary malignant bone tumour. However, the genetic basis for the pathogenesis of OS remains elusive. In this study, we uncovered the role of the histone methyltransferase NSD2 in regulating tumourigenesis and chemosensitivity in OS. We show that NSD2 knockdown leads to increased apoptosis in OS cells in vitro and in vivo. Additionally, NSD2 knockdown significantly enhances the efficacy of cisplatin against OS cells and accordingly inhibits properties associated with cancer stem cells (CSCs). Furthermore, RNA sequencing (RNAseq) and Gene Ontology (GO) analysis revealed that NSD2 promotes transcription of genes associated with negative regulation of apoptotic signalling pathways and CSC properties. The results of chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) assays indicated that NSD2 knockdown leads to decreased H3K36me2 modification at BCL2 and SOX2 loci, thus inhibiting the transcription of these two genes that are closely correlated with apoptosis, CSC properties and chemosensitivity in OS cells. Pathway analysis demonstrated that the ERK and AKT pathways mediate the regulation of OS progression and chemosensitivity by NSD2. Overall, our study is the first to uncover the function of NSD2 in OS chemosensitivity. NSD2 regulates the expression of the apoptosis regulatory proteins BCL2 and SOX2 through the ERK and AKT pathways. Our results suggest that NSD2 is a new target for combined chemotherapy and is a prognostic factor for OS.
Highlights
Osteosarcoma (OS) is one of the most common malignant bone tumours and arises primarily in children and adolescents[1]
NSD2, which belongs to the NSD family of histone lysine methyltransferases (HMTases)[8], is a histone methyltransferase that mediates dimethylation of histone 3 lysine 36 (H3K36me2); H3K36 methylation is typically a permissive marker associated with transcriptional activation[9,10,11]
The results indicated that NSD2 is upregulated in OS tissues compared with normal tissues and that NSD2 knockdown can enhance OS apoptosis and sensitize OS to cisplatin by directly decreasing H3K36me[2] levels at BCL2 and Sex-determining region Y-box 2 (SOX2) gene loci, as measured by chromatin immunoprecipitation (ChIP) analysis
Summary
Osteosarcoma (OS) is one of the most common malignant bone tumours and arises primarily in children and adolescents[1]. Since the 1970s, the introduction of Official journal of the Cell Death Differentiation Association. He et al Cell Death and Disease (2019)10:65. Epigenetic perturbations caused by histone methyltransferases or demethylases are recognized as important contributing factors to a variety of tumours[6], and epigenetic markers have frequently been found to be mutated or dysregulated in multiple cancers[7]. NSD2 was first reported to function as an oncogenic gene in multiple myeloma[12,13,14]. Whether NSD2 mediates chemosensitivity in OS has not been reported
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
