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NeuroD1 drives a KAT2A-FDFT1 signaling axis to promote cholesterol biosynthesis and hepatocellular carcinoma progression via histone H3K27 acetylation

Oncogene volume 44, pages 4017–4031 (2025)Cite this article

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A Correction to this article was published on 22 September 2025

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Abstract

Abnormal lipid metabolism is one of the hallmarks of cancer. Lipid metabolic reprogramming, which has been observed in various tumors, could participate in tumor occurrence, invasion, and metastasis of tumors by regulating various carcinogenic signaling pathways. However, the molecular mechanism that regulates tumor cell lipid metabolic reprogramming has not been fully elucidated. Recent studies revealed that neurogenic differentiation factor 1 (NeuroD1) is upregulated in a variety of tumor cells, and is associated with tumorigenesis and poor prognosis. However, its role in tumor cell lipid metabolism remains unclear. Here, we found that NeuroD1 is highly expressed in hepatocellular carcinoma (HCC) cells and is associated with tumor cell cholesterol biosynthesis. We found that NeuroD1 enhances HCC cell cholesterol biosynthesis, leading to an increase in their viability. Mechanistically, NeuroD1 binds to the promoter of farnesyl diphosphate farnesyl transferase 1 (FDFT1), thereby activating its transcription activity. Furthermore, NeuroD1 can promote FDFT1 transcription through lysine acetyltransferase 2A-mediated H3K27 acetylation. Subsequently, we found that NeuroD1/FDFT1-mediated cholesterol biosynthesis is critical to the tumorigenic potential of HCC cells. These findings not only identify NeuroD1 as a regulator of lipid metabolism in tumor cells, but also reveal a novel molecular mechanism underlying its carcinogenic function.

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Fig. 1: NeuroD1 increases HCC cell lipid metabolism.
Fig. 2: NeuroD1 increases HCC cell cholesterol biosynthesis.
Fig. 3: NeuroD1 positively regulates FDFT1.
Fig. 4: NeuroD1 promotes cholesterol biosynthesis by upregulating FDFT1.
Fig. 5: NeuroD1 directly regulates FDFT1 transcription.
Fig. 6: NeuroD1 induces H3K27Ac in the FDFT1 promoter region and promotes FDFT1 transcription.
Fig. 7: NeuroD1/FDFT1-driven cholesterol biosynthesis is crucial for tumor initiation.
Fig. 8: Schematic diagram showing the role of NeuroD1/FDFT1 axis on HCC cells cholesterol biosynthesis and tumorigenesis.

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Data availability

All data supporting the findings of this study can be freely accessed by any researcher for non-commercial purposes upon reasonable request.

Change history

  • 15 September 2025

    The original online version of this article was revised:In this article, the order in which the authors appeared in the author list was incorrectly given as Zheng Wu, Wei Duan, Ying Xiong, Jingyi Liu, Xinpeng Wen, Fuqiang Zhao, Debing Xiang, Shourong Wu, Vivi Kasim and Jian Wang where it should have been Zheng Wu, Wei Duan, Ying Xiong, Jingyi Liu, Xinpeng Wen, Fuqiang Zhao, Debing Xiang, Jian Wang, Vivi Kasim, and Shourong Wu. This was a mistake on the publishers end. The publisher apologies for the inconvenience.

  • 22 September 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-025-03574-y

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82173029 (SW), 32270778 (VK), and 82372655 (SW)), and the Talent Project of Chongqing University Jiangjin Hospital (2024LJXM005 (JW)).

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Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering; Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing University, Chongqing, China

    Zheng Wu, Wei Duan, Ying Xiong, Jingyi Liu, Xinpeng Wen, Fuqiang Zhao, Debing Xiang, Jian Wang, Vivi Kasim & Shourong Wu

  2. The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China

    Zheng Wu, Wei Duan, Ying Xiong, Vivi Kasim & Shourong Wu

  3. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, China

    Vivi Kasim & Shourong Wu

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  1. Zheng Wu
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Contributions

SW, VK, and JW conceived and designed the project, analyzed and interpreted the experimental results, and wrote the manuscript; ZW performed most of the experiments; analyzed and interpreted the experimental results, and wrote the manuscript; WD, YX, JL, XW, FZ, and DX analyzed and interpreted the data. DX and JW collected human clinical samples and performed clinical samples analysis. XW and FZ designed shRNA target sites and analyzed part of the data.

Corresponding authors

Correspondence to Jian Wang, Vivi Kasim or Shourong Wu.

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The authors declare no competing interests.

Ethical approval and consent to participate

Animal studies were approved by the Institutional Ethics Committee of Chongqing University Cancer Hospital (Permit No. SYXK-2021-0001). All animal experiments conformed to the Guidelines for the Care and Use of Laboratory Animals of the Chongqing University Cancer Hospital. For clinical HCC samples, prior patients’ written informed consents were obtained. The studies were approved by the Institutional Research Ethics Committee of Chongqing University Cancer Hospital (Permit No. CZLS2021292-A), and conducted in accordance with Declaration of Helsinki.

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Wu, Z., Duan, W., Xiong, Y. et al. NeuroD1 drives a KAT2A-FDFT1 signaling axis to promote cholesterol biosynthesis and hepatocellular carcinoma progression via histone H3K27 acetylation. Oncogene 44, 4017–4031 (2025). https://doi.org/10.1038/s41388-025-03534-6

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