Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
J Biochem Mol Toxicol. 2024 Jan;38(1):e23537. doi: 10.1002/jbt.23537. Epub 2023 Sep 13.
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.
越来越多的证据表明，精氨酸甲基转移酶-1（PRMT1）是多种恶性肿瘤包括骨肉瘤（OS）的癌基因。本研究旨在探讨 PRMT1 在 OS 中的潜在机制。检测了 PRMT1 或支链氨基酸转氨酶 1（BCAT1）对 OS 细胞体外增殖、侵袭、自噬和凋亡的影响。此外，通过染色质免疫沉淀和定量逆转录 PCR 检测评估了 PRMT1 对 c-Myc 的分子调控或 BCAT1 对 c-Myc 的反式激活。通过异种移植肿瘤模型检测了 PRMT1 的体内作用。结果表明，PRMT1 在 OS 组织和细胞中强烈上调。PRMT1 的上调显著增加了 OS 细胞的体外增殖和侵袭，并减少了细胞凋亡，而 PRMT1 沉默则显示出相反的效果。顺铂是最有效的化疗药物之一，通过诱导 PRMT1 的表达来降低顺铂敏感性，从而提高细胞存活率。同时，顺铂诱导的 PRMT1 表达上调通过抑制 mTOR 信号通路引起明显的自噬诱导和自噬介导的细胞凋亡，自噬抑制剂 3-甲基腺嘌呤或 PRMT1 沉默可逆转这种作用。PRMT1 可以激活 c-Myc 转录并增加 c-Myc 介导的 BCAT1 表达。此外，BCAT1 的过表达抵消了 PRMT1 敲低对细胞增殖、侵袭和凋亡的影响。值得注意的是，PRMT1 缺乏抑制体内肿瘤生长。PRMT1 通过 c-Myc/BCAT1 轴促进 OS 细胞的增殖和侵袭，抑制细胞凋亡，降低化疗敏感性，可能成为治疗 OS 的潜在靶点。
