Related Experiment Video
Updated: Jan 13, 2026
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Targeting the METTL3/PCNA axis with STM2457 overcomes cisplatin resistance in osteosarcoma
Hua Yu1, Shaoxing Li2, Jinwang Liu1
1Department of Orthopedics, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
Background:
Cisplatin resistance represents a major clinical challenge in osteosarcoma (OS), often leading to treatment failure and poor patient prognosis. The underlying molecular mechanisms are complex and incompletely understood. This study investigates the role of the RNA methyltransferase methyltransferase-like 3 (METTL3) and its associated N6-methyladenosine (m6A) modification in driving cisplatin resistance, with a specific focus on the METTL3-m6A-proliferating cell nuclear antigen (PCNA) regulatory axis as a potential therapeutic target.
Methods:
Cisplatin-resistant human OS cell lines (MG-63/DDP, U2OS/DDP) were used. The effects of the selective METTL3 inhibitor STM2457, both alone and in combination with cisplatin, on cell viability, apoptosis, and migration were evaluated using Cell Counting Kit-8 (CCK-8) assay, immunofluorescence staining for cleaved Caspase-3, and vimentin expression, respectively. Mechanistic investigations included quantification of global m6A levels, analysis of PCNA messenger RNA (mRNA) stability via actinomycin D assay, and western blot for protein expression. Functional roles were validated using small interfering RNA-mediated PCNA knockdown and plasmid-based PCNA overexpression. Drug interaction was analyzed using the combination index (CI) method.
Results:
STM2457 monotherapy significantly and dose-dependently suppressed cell proliferation and migration in cisplatin-resistant OS cells. Furthermore, STM2457 demonstrated strong synergistic effects with cisplatin (CI <1), markedly enhancing apoptosis induction. At the molecular level, STM2457 inhibited METTL3 catalytic activity, leading to a significant reduction in global m6A RNA methylation. This resulted in the destabilization of PCNA mRNA and a consequent decrease in PCNA protein levels. Knockdown of PCNA effectively mimicked the anti-tumor effects of STM2457, whereas forced overexpression of PCNA attenuated the efficacy of STM2457 and partially restored the cisplatin-resistant phenotype.
Conclusions:
Our findings demonstrate that STM2457 overcomes cisplatin resistance in OS by targeting the METTL3-m6A-PCNA axis, thereby disrupting a key DNA repair and cell survival pathway. Pharmacological inhibition of METTL3 represents a novel and promising epigenetic strategy for resensitizing chemoresistant OS, supporting its potential for future clinical development.
Insights
This study shows that inhibiting methyltransferase-like 3 (METTL3) with STM2457 overcomes cisplatin resistance in osteosarcoma by targeting the METTL3-N6-methyladenosine (m6A)-proliferating cell nuclear antigen (PCNA) pathway. This epigenetic strategy resensitizes chemoresistant osteosarcoma cells to cisplatin treatment.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Cisplatin resistance is a major hurdle in osteosarcoma (OS) treatment, leading to poor patient outcomes.
- The molecular mechanisms driving this resistance are not fully understood.
- This study focuses on the role of methyltransferase-like 3 (METTL3) and N6-methyladenosine (m6A) modification in OS cisplatin resistance.
Purpose of the Study:
- To investigate the role of the METTL3-m6A-proliferating cell nuclear antigen (PCNA) axis in cisplatin resistance in osteosarcoma.
- To evaluate the efficacy of the METTL3 inhibitor STM2457 in overcoming cisplatin resistance.
- To explore STM2457 as a potential therapeutic target for chemoresistant osteosarcoma.
Main Methods:
- Utilized cisplatin-resistant human osteosarcoma (OS) cell lines (MG-63/DDP, U2OS/DDP).
- Assessed the effects of STM2457 (alone and with cisplatin) on cell viability, apoptosis, and migration.
- Investigated molecular mechanisms including m6A levels, PCNA mRNA stability, and protein expression, validated by PCNA knockdown/overexpression.
Main Results:
- STM2457 monotherapy suppressed proliferation and migration in cisplatin-resistant OS cells.
- STM2457 showed synergistic effects with cisplatin, enhancing apoptosis.
- STM2457 reduced m6A levels, destabilized PCNA mRNA, and decreased PCNA protein, mimicking PCNA knockdown effects.
Conclusions:
- STM2457 overcomes cisplatin resistance in OS by targeting the METTL3-m6A-PCNA axis, disrupting DNA repair and survival pathways.
- Pharmacological inhibition of METTL3 is a promising epigenetic strategy to resensitize chemoresistant OS.
- This approach holds potential for future clinical development in treating refractory osteosarcoma.
