Abstract
Osteosarcoma (OS) is the most common bone malignancy in adolescents and has poor clinical outcomes. Protein arginine methyltransferase 5 (PRMT5) has recently been shown to be aberrantly expressed in various cancers, yet its role in OS remains elusive. Here, we found that PRMT5 was overexpressed in OS and its overexpression predicted poor clinical outcomes. PRMT5 knockdown significantly triggered pronounced senescence in OS cells, as evidenced by the increase in senescence-associated β-galactosidase (SA-β-gal)-stained cells, induction of p21 expression, and upregulation of senescence-associated secretory phenotype (SASP) gene expression. In addition, we found that PRMT5 plays a key role in regulating DNA damaging agents-induced OS cell senescence, possibly, via affecting the repair of DNA damage. Furthermore, we found that TXNIP acts as a key factor mediating PRMT5 depletion-induced DNA damage and cellular senescence. Mechanistically, TRIM21, which interacts with PRMT5, was essential for the regulation of TXNIP/p21 expression. In summary, we propose a model in which PRMT5, by interaction with TRIM21, plays a key role in regulating the TXNIP/p21 axis during senescence in OS cells. The present findings suggest that PRMT5 overexpression in OS cells might confer resistance to chemotherapy and that targeting the PRMT5/TRIM21/TXNIP signaling may enhance the therapeutic efficacy in OS.
Highlights
Osteosarcoma (OS) is the most common primary bone malignancy and occurs primarily in children and adolescents [1, 2]
We explored whether Protein arginine methyltransferase 5 (PRMT5) plays a role in regulating senescence of OS cells with or without the DNA damaging stress elicited by the most common first-line chemotherapeutic drug, CDDP
Several lines of evidence supporting the fact that PRMT5 is essential for regulating CDDP-induced OS cell senescence: firstly, at the basal level, PRMT5 knockdown significantly increases the number of senescent cells in OS and induces the senescence-associated secretory phenotype (SASP) gene expression, through a mechanism involving p21 expression; while ectopic expression of PRMT5 suppresses PRMT5 knockdown-induced cellular senescence
Summary
Osteosarcoma (OS) is the most common primary bone malignancy and occurs primarily in children and adolescents [1, 2]. Several epigenetic enzymes such as DNA methyltransferase 1 (DNMT1), enhancer of zeste homolog 2 (EZH2) and nuclear receptor-binding SET domain-containing (NSD), have been demonstrated to play a crucial role in OS, and targeting these enzymes enhanced OS cell apoptosis and chemosensitivity [4,5,6]. Targeting these enzymes in combination with chemotherapy might shed light on the treatment of OS
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