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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 Li1, Kui-Leung Tong1, Jun-Lei Lu2, Jie-Bin Lin3, Zhen-Yan Li1, Yuan Sang4, Abdelmoumin Ghodbane1, Xue-Juan Gao2, Man-Seng Tam5, Chang-Deng Hu6,7, Huan-Tian Zhang1, Zhen-Gang Zha1
  • 1Institute of Orthopedic Diseases and Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, Guangdong, China
  • 2Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou 510632, Guangdong, China
  • 3Department of Orthopedics, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
  • 4Department of Orthopaedic Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong, China
  • 5IAN WO Medical Center, Macao Special Administrative Region, Macao 999078, China
  • 6Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
  • 7Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
Received: June 14, 2019Accepted: January 10, 2020Published: February 5, 2020
https://doi.org/10.18632/aging.102760

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.