2. Academic Validation
  3. MARCH8/NSUN6/ROS-mediated DNA damage positive feedback loop regulates cisplatin resistance in osteosarcoma

MARCH8/NSUN6/ROS-mediated DNA damage positive feedback loop regulates cisplatin resistance in osteosarcoma

  • Cell Death Differ. 2025 Jul 19. doi: 10.1038/s41418-025-01544-1.
Mingyu He # 1 2,  Tao Li # 2,  Ao Wang # 2,  Ying Liu 2,  Xinyue Wang 2,  Ziwen Liu 3,  Jiajie Xie 1,  Yanquan Wang 2,  Yusheng Wang 4,  Zijing Ren 1,  Shiyu Ge 2,  Lei Yang 5 6 7,  Ye Yuan 8
Affiliations

Affiliations

  • 1 Department of Pharmacy (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, China.
  • 2 Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
  • 3 Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 4 NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 5 NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, China. yangray83@vip.qq.com.
  • 6 Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, China. yangray83@vip.qq.com.
  • 7 Key Laboratory of Hepatosplenic Surgery of Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China. yangray83@vip.qq.com.
  • 8 Department of Pharmacy (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, China. yuanye_hmu@126.com.
  • # Contributed equally.
PMID: 40683951 DOI: 10.1038/s41418-025-01544-1
Abstract

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and is often characterized by resistance to chemotherapy. Although RNA 5‑methylcytosine (m5C) modification is known to contribute to tumor progression, its exact role in osteosarcoma drug resistance remains poorly understood. Here, we identify NOP2/Sun RNA methyltransferase family member 6 (NSUN6) as an m5C methyltransferase that positively correlates with osteosarcoma progression. Mechanistically, the E3 ubiquitin Ligase membrane‑associated RING‑CH‑type finger 8 (MARCH8) ubiquitinates NSUN6 at Lys271 and Lys462, leading to its proteasomal degradation. Reduced NSUN6 expression lowers m5C modification on peroxisomal biogenesis factor 1 (PEX1) and peroxisomal biogenesis factor 3 (PEX3) mRNAs, destabilizing them through loss of binding by the m5C reader YBX1. In turn, this downregulates peroxisome synthesis and catalase (CAT) protein production, causing increased intracellular Reactive Oxygen Species (ROS), DNA damage, and heightened sensitivity of osteosarcoma cells to cisplatin. Furthermore, elevated ROS levels reinforce NSUN6 ubiquitination and degradation by enhancing the NSUN6-MARCH8 interaction, establishing a positive feedback loop. Collectively, these findings highlight an intricate NSUN6-m5C-YBX1-PEXs signaling axis that governs peroxisome biogenesis, ROS accumulation, and cisplatin responsiveness in osteosarcoma. Our work not only clarifies the role of m5C in osteosarcoma drug resistance but also offers a potential therapeutic angle for targeting NSUN6 and its peroxisome‑regulating network to overcome chemoresistance.

Figures
Products
Inhibitors & Agonists
Other Products