Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

Abstract

Increasing evidence indicated that protein arginine methyltransferase‐1 (PRMT1) is an oncogene in multiple malignant tumors, including osteosarcoma (OS). The aim of this study was to investigate the underlying mechanism of PRMT1 in OS. The effects of PRMT1 or BCAT1, branched‐chain amino acid transaminase 1 (BCAT1) on OS cell proliferation, invasion, autophagy, and apoptosis in vitro were examined. Moreover, molecular control of PRMT1 on c‐Myc or transactivation of BCAT1 on c‐Myc was assessed by chromatin immunoprecipitation and quantitative reverse transcription PCR assays. The effects of PRMT1 in vivo were examined with a xenograft tumor model. The results showed that PRMT1 was potently upregulated in OS tissues and cells. Upregulation of PRMT1 markedly increased OS cell proliferation and invasion in vitro and reduced cell apoptosis, whereas PRMT1 silencing showed the opposite effects. Cisplatin, one of the most effective chemotherapeutic drugs, improved cell survival rate by inducing the expression of PRMT1 to downregulate the cisplatin sensitivity. Meanwhile, the cisplatin‐induced upregulation of PRMT1 expression caused dramatically autophagy induction and autophagy‐mediated apoptosis by inactivating the mTOR signaling pathway, which could be reversed by 3‐methyladenine, an autophagy inhibitor, or PRMT1 silencing. PRMT1 could activate c‐Myc transcription and increase c‐Myc‐mediated expression of BCAT1. Furthermore, BCAT1 overexpression counteracted the effects of PRMT1 knockdown on cell proliferation, invasion, and apoptosis. Of note, deficiency of PRMT1 suppressed tumor growth in vivo. PRMT1 facilitated the proliferation and invasion of OS cells, inhibited cell apoptosis, and decreased chemotherapy sensitivity through c‐Myc/BCAT1 axis, which may become potential target in treating OS.

PRMT1 in human neoplasm: cancer biology and potential therapeutic target

“…Li et al’s study provides additional evidence of PRMT1’s role in promoting osteosarcoma at the translational level. It was found that PRMT1-mediated H4R3me2a could enhance c-Myc expression, activating the mTOR signaling pathway and promoting osteosarcoma progression [ 95 ]. Methylation of STAT3 at arginine 688 by PRMT1 promoted its transcriptional activation, contributing to osteosarcoma malignancy.…”