Targeting the METTL3/PCNA axis with STM2457 - Overcomes cisplatin resistance in osteosarcoma

Q: How were PCNA causal effects tested in the study?

PCNA knockdown mimicked STM2457’s anti-tumor effects, while PCNA overexpression attenuated STM2457 efficacy and partially restored the cisplatin-resistant phenotype.

Sep 30, 2026

Uploaded by Jake

Cisplatin resistance is a major clinical barrier in osteosarcoma, with complex molecular causes that remain incompletely understood. This study evaluates how the RNA methyltransferase METTL3 and m6A modification regulate cisplatin resistance through the METTL3-m6A-PCNA axis. Using cisplatin-resistant OS cell lines, the selective METTL3 inhibitor STM2457 suppresses proliferation and migration and strengthens cisplatin-induced apoptosis. Mechanistically, STM2457 reduces global m6A and destabilizes PCNA mRNA, lowering PCNA protein; PCNA knockdown mimics, while PCNA overexpression partially restores, the resistant phenotype.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Cisplatin resistance in osteosarcoma and PCNA

METTL3-mediated m6A as a therapeutic axis

Methods

Cell models and treatments

Functional and mechanistic assays

Results

STM2457 inhibits growth and migration

Synergy with cisplatin and apoptosis effects

METTL3 inhibition, m6A reduction, and PCNA regulation

Conclusions

Therapeutic implication of STM2457 targeting METTL3-m6A-PCNA axis

Key findings

Targeting the METTL3/PCNA axis with STM2457 overcomescisplatin resistance in osteosarcoma Hua Yu1\#, Shaoxing Li2\#, Jinwang Liu1 1Department of Orthopedics, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China; 2Department of Gynaecology and Obstetrics, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China Contributions: (I) Conception and design: H Yu, S Li; (II) Administrative support: J Liu; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: H Yu, S Li; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. \#These authors contributed equally to this work. Correspondence to: Jinwang Liu, PhD. Department of Orthopedics, the First Affiliated Hospital of Chengdu Medical College, 278 Baoguang Avenue, Xindu District, Chengdu 610500, China. Email: [liujinwang1984@163.com](liujinwang1984@163.com). 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 methyltransferaselike 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 Dassay, and western blot for protein expression. Functional roles were validated using small interfering RNAmediated 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. Keywords: Methyltransferase-like 3 (METTL3); STM2457; cisplatin resistance; osteosarcoma (OS); proliferating cell nuclear antigen (PCNA) Submitted Jul 02, 2025. Accepted for publication Oct 22, 2025. Published online Dec 05, 2025. doi: 10.21037/tcr-2025-1429 View this article at: [https://dx.doi.org/10.21037/tcr-2025-1429](https://dx.doi.org/10.21037/tcr-2025-1429) © AME Publishing Company. Transl Cancer Res 2025;14(12):8567-8578 | [https://dx.doi.org/10.21037/tcr-2025-1429](https://dx.doi.org/10.21037/tcr-2025-1429) 8568 Yu et al. STM2457 overcomes cisplatin resistance in OS Introduction Ost

FAQs

How were PCNA causal effects tested in the study?

PCNA knockdown mimicked STM2457’s anti-tumor effects, while PCNA overexpression attenuated STM2457 efficacy and partially restored the cisplatin-resistant phenotype.

Sep 30, 2026

Uploaded by Jake