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Regulation of cancer stem cell activity by thyroid hormone receptor β

Oncogene volume 41, pages 2315–2325 (2022)Cite this article

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Abstract

Increasing numbers of cancer stem cell markers have been recently identified. It is not known, however, whether a member of the nuclear receptor superfamily, thyroid hormone receptor β (TRβ), can function to regulate cancer stem cell (CSC) activity. Using anaplastic thyroid cancer cells (ATC) as a model, we highlight the role of TRβ in CSC activity. ATC is one of the most aggressive solid cancers in humans and is resistant to currently available therapeutics. Recent studies provide evidence that CSC activity underlies aggressiveness and therapeutic resistance of ATC. Here we show that TRβ inhibits CSC activity by suppressing tumor-sphere formation of human ATC cells and their tumor-initiating capacity. TRβ suppresses the expression of CSC regulators, including ALDH, KLF2, SOX2, b-catenin, and ABCG2, in ATC cell-induced xenograft tumors. Single-cell transcriptomic analysis shows that TRβ reduces CSC population in ATC-induced xenograft tumors. Analysis of The Cancer Genome Atlas (TCGA) database demonstrates that the inhibition of CSC capacity by TRβ contributes to favorable clinical outcomes in human cancer. Our studies show that TRβ is a newly identified transcription regulator that acts to suppress CSC activity and that TRβ could be considered as a molecular target for therapeutic intervention of ATC.

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Fig. 1: ATC exhibits high stemness, thereby facilitating its initiation and growth.
Fig. 2: TRβ attenuates capacity of CSCs.
Fig. 3: TRβ blocks the tumor-initiating capacity of CSCs in ATC.
Fig. 4: TRβ reduces both capacity and population size of CSCs in vivo.
Fig. 5: T3 potentiates transcriptional inhibition of ALDH by TRβ in ATC cells.
Fig. 6: TRβ is negatively associated with cancer stemness.

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Acknowledgements

We thank Drs. Zachary Rae, Michael Kelly, and Kimia Dadkhah for carrying out single-cell RNA sequencing at the Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory (Leidos Biomed), NCI. We also thank Joelle Mornini, NIH Library, for manuscript editing assistance.

Funding

This research is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Woo Kyung Lee, Xuguang Zhu, Sunmi Park, Li Zhao & Sheue-yann Cheng

  2. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Yuelin Jack Zhu & Paul Meltzer

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Contributions

Conception and designs were performed by SC and WKL; Development of methodology and acquisition of data were carried out by WKL, XZ, SP, LZ, and JZ; Analysis and interpretation of data were performed by WKL, XZ, SP, JZ, PM, and SC; Writing, review, and/or revision were performed by SC and WKL. Administrative, technical, or material support were performed by LZ, PM, and SC.

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Correspondence to Sheue-yann Cheng.

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Lee, W.K., Zhu, X., Park, S. et al. Regulation of cancer stem cell activity by thyroid hormone receptor β. Oncogene 41, 2315–2325 (2022). https://doi.org/10.1038/s41388-022-02242-9

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