Research Paper Volume 12, Issue 3 pp 2507—2529

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

Yu-Hang Li 1, , Kui-Leung Tong 1, , Jun-Lei Lu 2, , Jie-Bin Lin 3, , Zhen-Yan Li 1, , Yuan Sang 4, , Abdelmoumin Ghodbane 1, , Xue-Juan Gao 2, , Man-Seng Tam 5, , Chang-Deng Hu 6, 7, , Huan-Tian Zhang 1, , Zhen-Gang Zha 1, ,

  • 1 Institute of Orthopedic Diseases and Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, Guangdong, China
  • 2 Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou 510632, Guangdong, China
  • 3 Department of Orthopedics, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
  • 4 Department of Orthopaedic Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong, China
  • 5 IAN WO Medical Center, Macao Special Administrative Region, Macao 999078, China
  • 6 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
  • 7 Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA

received: June 14, 2019 ; accepted: January 10, 2020 ; published: February 5, 2020 ;

https://doi.org/10.18632/aging.102760
How to Cite

Copyright © 2020 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

OS: osteosarcoma; CDDP: cisplatin; DNMT1: DNA methyltransferase 1; EZH2: enhancer of zeste homolog 2; NSD: nuclear receptor binding SET domain containing; PRMT5: protein arginine methyltransferase 5; PKC: the protein kinase C; NF-Y: nuclear transcription factor Y; CHIP: carboxyl terminus of heat shock cognate 70-interacting protein; DDR: DNA damage response; Fen1: flap structure-specific endonuclease 1; RUVBL1: RuvB-like AAA ATPase 1; SA-β-gal: senescence-associated β-galactosidase; SASP: senescence-associated secretory phenotypes; TXNIP: thioredoxin-interacting protein; TMAs: tissue microarrays; IHC: immunohistochemistry; OTM: olive tail moment; EdU: 5-Ethynyl-2'-deoxyuridine; DSBs: double-strand breaks; SC: scramble control; BiFC: bimolecular fluorescence complementation; co-IP: coimmunoprecipitation; Dox: doxycycline; DMF: dimethylformamide; PBS: phosphate-buffered saline; PBST: phosphate-buffered saline containing 0.1% Tween 20; RT: room temperature; SDs: standard deviations; PMSF: phenylmethylsulfonyl fluoride; PVDF: polyvinylidene difluoride membranes; PI: propidium iodide; DAPI: 4’,6-diamidino-2-phenylindole; n.s: no significant.

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