Loss of YTHDF1 suppresses the progression of malignant rhabdoid tumor of the kidney - by regulating Glutathione S-transferase Mu 2 (GSTM2)

Sep 24, 2026

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Malignant rhabdoid tumor of the kidney (MRTK) is a rare pediatric renal cancer with poor outcomes. Although germline SMARCB1 mutations are viewed as a primary driver, somatic epigenetic changes likely contribute to MRTK development. YTHDF1, an m6A reader implicated in tumorigenesis, had limited study in pediatric contexts. This work examines how YTHDF1 loss affects MRTK growth, chemoresistance, and ferroptosis-related molecular signaling.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Introduction

Epigenetic alterations and m6A

Cell Biol Toxicol (2025) 41:96 [https://doi.org/10.1007/s10565-025-10049-z](https://doi.org/10.1007/s10565-025-10049-z) Loss of YTHDF1 suppresses the progression of malignant rhabdoid tumor of the kidney by regulating Glutathione S‑transferase Mu 2 (GSTM2) Qian‑Wen Xiong · Yuntao Liu · Min He · Xiao‑Die Shen · Manli Zhao · Shuang‑Ai Liu · Gensheng Zhang · Qian Liu · Jinhu Wang · Wan‑Xin Peng Received: 15 October 2024 / Accepted: 30 May 2025 © The Author(s) 2025 Abstract Background Malignant rhabdoid tumor of the kidney (MRTK) is a rare renal tumor with poor prognosis. While germline mutations of SMARCB1 are considered to be the primary cause of MRTK, emerging evidence suggests that somatic epigenetic changes also play a vital role in the development and progression of MRTK. YTHDF1, an m6A reader protein, has been implicated in regulation of tumorigenesis by influencing RNA translation and stability in several | Qian-Wen Xiong, Yuntao Liu and Min He contributed equally to this work. | | --- | | Supplementary Information The online version contains supplementary material available at [https://doi](https://doi). org/10.1007/s10565-025-10049-z. | Q.-W. Xiong · M. He · X.-D. Shen · S.-A. Liu · J. Wang (*) Department of Surgical Oncology, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China [e-mail: wjh@zju.edu.cn](e-mail: wjh@zju.edu.cn) Q.-W. Xiong · W.-X. Peng (*) Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China [e-mail: pengwanxin@gmail.com](e-mail: pengwanxin@gmail.com) Y. Liu Institute of Neuroscience, Basic Medicine College of Chongqing Medical University, Chongqing, China adult cancers. However, the exploration of the role of YTHDF1 in pediatric cancer, especially MRTK, remains limited. Methods In this study, CRISPR/Cas9 was employed to knockout (KO) YTHDF1 in G401 cells. The impact of YTHDF1 on the cell growth and chemoresistance were assessed using CCK-8 assays. Western blot and qRT-PCR were used to determine the changes in ferroptosis marker gene expression. Additionally, 4D-label free quantitative proteomics was conducted to uncover alterations by YTHDF1 deletion. Results We observed that the deletion of YTHDF1 in the MRTK cell line led to a significant reduction in malignancy-associated characteristics, including decreased cell motility, invasive growth, and chemoresistance. Quantitative proteomic analysis revealed M. Zhao Department of Pathology, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China G. Zhang Department of Nephrology, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China Q. Liu School of Basic Medical Science, Chongqing University of Chinese Medicine, Chongqing, China that the glutathione-related signaling pathway was notably affected by YTHDF1 KO. Specifically, YTHDF1 KO resulted in a reduction of both mRNA and protein levels of Glutathione S-Transferase Mu 2 (GSTM2), a phase II metabolizing enzyme responsible for conjugating glutathione to electrophilic compounds. The decrease in GSTM2 levels following YTHDF1 KO increased the susceptibility of MRTK cells to ferroptosis. Notably, overexpression of GSTM2 in YTHDF1 KO cells partially restored the oncogenic phenotype of MRTK cells, underscoring its role in MRTK progression. Conclusions In summary, our findings provide new insights into the molecular mechanisms driving MRTK progression, highlighting YTHDF1 and GSTM2 as potential therapeutic targets for this aggressive pediatric renal tumor. Keywords MRTK · YTHDF1 · M6 A · GSTM2 · Ferroptosis Abbreviations 4

FAQs

What does loss of YTHDF1 do in malignant rhabdoid tumor of the kidney (MRTK) cells?

YTHDF1 deletion significantly reduces malignancy-associated behaviors, including decreased cell motility, invasive growth, and chemoresistance.

How was YTHDF1 function studied in the paper?

CRISPR/Cas9 was used to knockout YTHDF1 in G401 cells, with CCK-8 assays for growth and chemoresistance, Western blot and qRT-PCR for marker changes, and 4D-label free quantitative proteomics to map alterations.

Why does YTHDF1 deletion increase susceptibility to ferroptosis?

YTHDF1 knockout lowers both mRNA and protein levels of GSTM2, reducing the glutathione-related signaling capacity and thereby increasing MRTK cell sensitivity to ferroptosis.

Sep 24, 2026

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