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Capicua restricts cancer stem cell-like properties in breast cancer cells

Oncogene volume 39, pages 3489–3506 (2020)Cite this article

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Abstract

Cancer stem cells (CSCs) play a central role in cancer initiation, progression, therapeutic resistance, and recurrence in patients. Here we present Capicua (CIC), a developmental transcriptional repressor, as a suppressor of CSC properties in breast cancer cells. CIC deficiency critically enhances CSC self-renewal and multiple CSC subpopulations of breast cancer cells without altering their growth rate or invasiveness. Loss of CIC relieves repression of ETV4 and ETV5 expression, consequently promoting self-renewal capability, EpCAM+/CD44+/CD24low/− expression, and ALDH activity. In xenograft models, CIC deficiency significantly increases CSC frequency and drives tumor initiation through derepression of ETV4. Consistent with the experimental data, the CD44high/CD24low CSC-like feature is inversely correlated with CIC levels in breast cancer patients. We also identify SOX2 as a downstream target gene of CIC that partly promotes CSC properties. Taken together, our study demonstrates that CIC suppresses breast cancer formation via restricting cancer stemness and proposes CIC as a potential regulator of stem cell maintenance.

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Fig. 1: CIC suppresses self-renewal capability in breast cancer cells.
Fig. 2: CIC regulates BCSC-like features.
Fig. 3: Deficiency of CIC relieves repression of ETV4 and ETV5 expression in breast cancer cells.
Fig. 4: ETV4 and ETV5 enhance BCSC-like properties.
Fig. 5: CIC deficiency-mediated promotion of BCSC-like features is due to derepression of ETV4 and ETV5.
Fig. 6: SOX2 is a direct target of CIC in MCF-7 cells.

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Acknowledgements

We thank the Lee lab members for helpful discussions on this study as well as helping to conduct the experiments. This work was supported by grants from the National Research Foundation (NRF) of Korea (2017R1A5A1015366 and 2018R1A2B2004416 to YL). JY and DK were supported by the BK21 Plus Program (Program of Bio-Molecular Function, POSTECH).

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  1. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, 37673, Republic of Korea

    Jeehyun Yoe, Donghyo Kim, Sanguk Kim & Yoontae Lee

  2. Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, 37673, Republic of Korea

    Sanguk Kim & Yoontae Lee

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JY and YL designed the study. JY performed the experiments. DK and SK analyzed the TCGA datasets. JY wrote and YL edited the manuscript.

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Correspondence to Yoontae Lee.

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Yoe, J., Kim, D., Kim, S. et al. Capicua restricts cancer stem cell-like properties in breast cancer cells. Oncogene 39, 3489–3506 (2020). https://doi.org/10.1038/s41388-020-1230-7

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