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Targeting FTO shows therapeutic potential in esophageal squamous cell carcinoma by modulating microRNA biogenesis

Oncogene (2026)Cite this article

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Abstract

N6-methyladenosine (m6A) RNA modification is a pivotal post-transcriptional regulator of RNA metabolism and cancer progression. Fat mass and obesity-associated protein (FTO), an m6A demethylase, has emerged as a potent oncogenic driver across multiple malignancies. In this study, we demonstrate that FTO directly demethylates the primary transcripts of the miR-200b/a/429 cluster, thereby impeding DGCR8-mediated recognition and processing. The ensuing reduction in mature tumor-suppressive miR-200b/a/429 relieves repression of a suite of downstream targets intimately linked to metastasis and cell proliferation, ultimately accelerating tumor growth and lymph-node dissemination in esophageal squamous cell carcinoma (ESCC). Pharmacologic inhibition of FTO restores miR-200b/a/429 cluster expression and partially rescues the oncogenic phenotype elicited by FTO overexpression. Collectively, our findings uncover a previously unrecognized FTO-m6A-miR-200b/a/429 axis that propels ESCC progression and highlight FTO as a promising therapeutic target for patients with ESCC.

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Fig. 1: FTO is upregulated in ESCC and correlated with poor prognosis of patients.
Fig. 2: FTO promotes proliferation and metastasis of esophageal squamous cell carcinoma (ESCC).
Fig. 3: The oncogenic role of FTO in ESCC depends on its m⁶A demethylase activity.
Fig. 4: FTO facilitates tumor progression by suppressing the maturation of the miR-200b cluster via m⁶A demethylation.
Fig. 5: Multiple proliferation- and EMT-related factors are downstream targets of the FTO/miR-200b cluster axis.
Fig. 6: FTO inhibitors suppress the progression of ESCC.
Fig. 7: FTO inhibitors rescue miR-200b cluster processing via m⁶A-dependent mechanisms and attenuate downstream gene expression.

Data availability

All raw data supporting the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Custom R scripts used for data processing, statistical analysis, and figure generation are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to express our appreciation to Dr. Mei Qi and Dr. Duobo Shi at Qilu Hospital of Shandong University for their assistance in the pathological evaluation. This study was supported by the Natural Science Foundation of Shandong Province (No. ZR2021MH106 and No. ZR2023QH230).

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  1. These authors contributed equally: Wei Zhou, Chunyan Wang.

Authors and Affiliations

  1. Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China

    Wei Zhou, Chunyan Wang, Changhao Li, Pengxiang Chen, Yuchen Liu, Hongyuan Mao, Pengfei Zhu, Yuxiao Gong, Yufeng Cheng & Lin Zhang

  2. Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Wei Zhou

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Contributions

LZ and YC performed study concept, design and supervision; WZ and CW designed and performed most of the experiments; CL and PC participated in some experiments; YL helped to analyze RIP-qPCR data; HM, PZ, and YG collected clinical samples; WZ and CW created figures, performed statistical analysis and wrote the paper; LZ revised the paper. WZ, CW, and YC supplemented the experiments according to the reviewers’ comments. All authors read and approved the final manuscript.

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Correspondence to Yufeng Cheng or Lin Zhang.

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The authors declare no competing interests.

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Written informed consent was obtained from all individual participants (or their legal guardians) prior to inclusion in the study, in accordance with the Declaration of Helsinki and the protocol approved by the Ethics Committee of Qilu Hospital, Shandong University.

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Zhou, W., Wang, C., Li, C. et al. Targeting FTO shows therapeutic potential in esophageal squamous cell carcinoma by modulating microRNA biogenesis. Oncogene (2026). https://doi.org/10.1038/s41388-026-03754-4

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