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Targeting CREB-binding protein (CBP) abrogates colorectal cancer stemness through epigenetic regulation of C-MYC

Cancer Gene Therapy volume 31, pages 1734–1748 (2024)Cite this article

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Abstract

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.

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Fig. 1: Differentiation of colorectal CSCs from hiPSCs.
Fig. 2: The in vivo tumorigenic ability of hiPSC-derived colorectal CSCs.
Fig. 3: The migration ability of hiPSC-derived colorectal CSCs in vitro and in vivo.
Fig. 4: Angiogenic properties of hiPSC-derived colorectal CSCs in vitro and in vivo.
Fig. 5: Upregulation of C-MYC was found in hiPSC-derived colorectal CSCs.
Fig. 6: Epigenetic regulation of the promoters of Yamanaka factors in hiPSC-derived colorectal CSCs.
Fig. 7: Inhibition of CBP attenuates the stemness of hiPSC-derived colorectal CSCs.

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The data presented in this study were generated by the authors and included in the article.

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Acknowledgements

We thank the Taiwan Human Disease Induced Pluripotent Stem Cell Service Consortium (Taiwan-iPSC consortium) for helping with iPSC generation. We are grateful to Dr. Ching-Chow Chen (Department and Graduate Institute of Pharmacology, National Taiwan University) for providing human CRC cells for this project. We also acknowledge Kuo-Tai Hua (Graduate Institute of Toxicology, National Taiwan University) for helping with shRNA lentiviral particle production. We thank the imaging core at the First Core Labs, National Taiwan University College of Medicine, for technical support in image acquisition and analysis. Thanks to the members of our laboratory for their contributions.

Funding

This work was financially supported by the National Science and Technology Council, Taiwan (109-2813-C-002-115-B, 111-2813-C-002-236-B, and 112-2320-B-002-028-MY3) and the National Taiwan University College of Medicine (111L4000 and 112L4000). The authors would like to express their gratitude to the National Taiwan University College of Medicine for facility support.

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  1. These authors contributed equally: Dai-Jung Chung, Chun-Hao Wang, Pin‑Jung Liu.

Authors and Affiliations

  1. Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Dai-Jung Chung, Chun-Hao Wang, Pin‑Jung Liu, Shang-Kok Ng, Cong-Kai Luo, Si-Han Jwo, Chin-Tzu Li, Dai-Yi Hsu, Chia-Chu Fan & Tzu-Tang Wei

  2. Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100225, Taiwan

    Chun-Hao Wang

  3. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan

    Pin‑Jung Liu

  4. School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan

    Chia-Chu Fan

  5. Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program in Chemical Biology and Molecular Biophysics (TIGP-CBMB), Academia Sinica, Taipei, 11529, Taiwan

    Tzu-Tang Wei

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Contributions

DJ Chung, CH Wang, PJ Liu, SK Ng, CK Luo, SH Jwo, CT Li, DY Hsu, and CC Fan performed the experiments, analyzed the data and created the figures. TT Wei designed the study and initiated the project. TT Wei supervised the research and wrote the manuscript. All the authors have read and approved the final manuscript.

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Correspondence to Tzu-Tang Wei.

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The authors declare that all methods were performed in accordance with the relevant guidelines and regulations. The procedures for collecting human blood samples were approved by the Institutional Review Board of the National Taiwan University Hospital. Signed informed consent was obtained from all participants. Additionally, the authors have obtained written informed consent for publication of the images.

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Chung, DJ., Wang, CH., Liu, P. et al. Targeting CREB-binding protein (CBP) abrogates colorectal cancer stemness through epigenetic regulation of C-MYC. Cancer Gene Ther 31, 1734–1748 (2024). https://doi.org/10.1038/s41417-024-00838-9

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