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Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression

Oncogene volume 43, pages 3121–3136 (2024)Cite this article

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Abstract

An increase in the total choline-containing compound content is a common characteristic of cancer cells, and aberrant choline metabolism in cancer is closely associated with malignant progression. However, the potential role of choline-induced global transcriptional changes in cancer cells remains unclear. In this study, we reveal that an elevated choline content facilitates hepatocellular carcinoma (HCC) cell proliferation by reprogramming Krüppel-like factor 5 (KLF5)-dominated core transcriptional regulatory circuitry (CRC). Mechanistically, choline administration leads to elevated S-adenosylmethionine (SAM) levels, inducing the formation of H3K4me1 within the super-enhancer (SE) region of KLF5 and activating its transcription. KLF5, as a key transcription factor (TF) of CRC established by choline, further transactivates downstream genes to facilitate HCC cell cycle progression. Additionally, KLF5 can increase the expression of choline kinase-α (CHKA) and CTP:phosphocholine cytidylyltransferase (CCT) resulting in a positive feedback loop to promote HCC cell proliferation. Notably, the histone deacetylase inhibitor (HDACi) vorinostat (SAHA) significantly suppressed KLF5 expression and liver tumor growth in mice, leading to a prolonged lifespan. In conclusion, these findings highlight the epigenetic regulatory mechanism of the SE-driven key regulatory factor KLF5 conducted by choline metabolism in HCC and suggest a potential therapeutic strategy for HCC patients with high choline content.

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Fig. 1: Choline promotes the proliferation and cell cycle progression of HCC cells in vitro.
Fig. 2: Choline reprograms the SE and CRC landscape in HCC cells.
Fig. 3: KLF5 is regulated by choline methyl group metabolism in a SE-driven manner.
Fig. 4: KLF5 promotes the proliferation and cell cycle progression of HCC cells in vitro.
Fig. 5: Choline and KLF5 regulate cell cycle-related genes, and KLF5 regulate choline phospholipid metabolism in turn.
Fig. 6: SAHA suppresses KLF5 and choline metabolism enzymes expression to inhibit liver tumor growth in mice.
Fig. 7: Choline metabolism and KLF5 expression are upregulated in HCC and are correlated with poor survival in HCC patients.

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Data availability

The data generated in this study are available within the article and its supplementary data files. The raw data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE262272.

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Acknowledgements

We are grateful for Prof. Lijian Hui’s gifts of hiHeps and Prof. Jian Xu’s gifts of the enCRISPRi plasmids. This work was supported by grants from the National Natural Science Foundation of China (82121004 and 81930123).

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  1. These authors contributed equally: Xinrong Li, Zhixiang Hu.

Authors and Affiliations

  1. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Xinrong Li, Zhixiang Hu, Qili Shi, Wenying Qiu, Yizhe Liu, Yanfang Liu, Shenglin Huang, Linhui Liang, Zhiao Chen & Xianghuo He

  2. Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China

    Shenglin Huang & Xianghuo He

  3. Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China

    Xianghuo He

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Contributions

X. He, Z. Chen and X. Li conceived and designed the study. X. Li, Z. Hu, W. Qiu and Y. Liu performed the experiments. X. Li, Q. Shi, Z. Chen, Y. Liu, S. Huang and L. Liang processed the data. X. Li and X. He wrote and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zhiao Chen or Xianghuo He.

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The animal experiments were conducted in strict accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of Fudan University Shanghai Cancer Center. Approval for these experiments was obtained under the following permission numbers: FUSCC-IACUC-2023121 and FUSCC-IACUC-2023278 (Shanghai, China). All methods were performed in accordance with the relevant guidelines and regulations.

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Li, X., Hu, Z., Shi, Q. et al. Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression. Oncogene 43, 3121–3136 (2024). https://doi.org/10.1038/s41388-024-03150-w

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