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PGC-1α promotes colorectal carcinoma metastasis through regulating ABCA1 transcription

Oncogene volume 42, pages 2456–2470 (2023)Cite this article

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Abstract

Colorectal cancer (CRC) is a highly aggressive cancer in which metastasis plays a key role. However, the mechanisms underlying metastasis have not been fully elucidated. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a regulator of mitochondrial function, has been reported as a complicated factor in cancer. In this study, we found that PGC-1α was highly expressed in CRC tissues and was positively correlated with lymph node and liver metastasis. Subsequently, PGC-1α knockdown was shown to inhibit CRC growth and metastasis in both in vitro and in vivo studies. Transcriptomic analysis revealed that PGC-1α regulated ATP-binding cassette transporter 1 (ABCA1) mediated cholesterol efflux. Mechanistically, PGC-1α interacted with YY1 to promote ABCA1 transcription, resulting in cholesterol efflux, which subsequently promoted CRC metastasis through epithelial-to-mesenchymal transition (EMT). In addition, the study identified the natural compound isoliquiritigenin (ISL) as an inhibitor that targeted ABCA1 and significantly reduced CRC metastasis induced by PGC-1α. Overall, this study sheds light on how PGC-1α promotes CRC metastasis by regulating ABCA1-mediated cholesterol efflux, providing a basis for further research to inhibit CRC metastasis.

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Fig. 1: PGC-1α expression is upregulated in CRC and positively associates with clinicopathological features.
Fig. 2: PGC-1α promotes CRC cell proliferation, colony formation, migration, invasion and angiogenesis.
Fig. 3: PGC-1α promotes CRC growth and metastasis through EMT.
Fig. 4: PGC-1α regulates ABCA1, and ABCA1 promotes CRC metastasis.
Fig. 5: PGC-1α regulates CRC metastasis via ABCA1.
Fig. 6: PGC-1α interacts with YY1 to regulate ABCA1 transcription.
Fig. 7: The ABCA1 inhibitor ISL suppresses PGC-1α-induced CRC metastasis, and ISL synergistically inhibits CRC metastasis with silenced PGC-1α.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81572972), the Supporting Plan of Scientific and Technological Innovation Team in Universities of Henan Province (20IRTSTHN029), the Scientific and Technological Research Project of Henan Province (212102310250).

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  1. These authors contributed equally: Wei Chen, Qiushuang Zhang.

Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, P. R. China

    Wei Chen, Qiushuang Zhang, Xiaoshuo Dai, Xinhuan Chen, Yihuan Chen, Kai Zhang, Xiaoxuan Duan, Yan Qiao, Jimin Zhao, Fang Tian, Kangdong Liu, Ziming Dong & Jing Lu

  2. Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, P. R. China

    Xinhuan Chen, Yan Qiao, Jimin Zhao, Fang Tian, Kangdong Liu, Ziming Dong & Jing Lu

  3. State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, P. R. China

    Xinhuan Chen, Yan Qiao, Jimin Zhao, Fang Tian, Kangdong Liu, Ziming Dong & Jing Lu

  4. Department of Pathology, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan Province, 450003, P. R. China

    Chengjuan Zhang & Ruihua Bai

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Contributions

WC, QSZ and JL contributed to the design of the experiments. WC, QSZ, XSD, YHC, KZ and XXD performed the experiments and analyzed the data. XHC, CJZ and RHB helped to perform the experiments and contributed to the software analysis. YQ, JMZ, FT, KDL and ZMD helped to perform material preparation and data analysis. WC and QSZ wrote the manuscript. JL revised the manuscript and supervised the study.

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Correspondence to Jing Lu.

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Chen, W., Zhang, Q., Dai, X. et al. PGC-1α promotes colorectal carcinoma metastasis through regulating ABCA1 transcription. Oncogene 42, 2456–2470 (2023). https://doi.org/10.1038/s41388-023-02762-y

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