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G9a/RelB regulates self-renewal and function of colon-cancer-initiating cells by silencing Let-7b and activating the K-RAS/β-catenin pathway

Nature Cell Biology volume 18, pages 9931005 (2016) | Download Citation

  • This article was retracted on 23 December 2016

This article has been updated

Abstract

Epigenetic reprogramming has been associated with the functional plasticity of cancer-initiating cells (CICs); however, the regulatory pathway has yet to be elucidated. A siRNA screen targeting known epigenetic genes revealed that G9a profoundly impairs the chemo-resistance, self-renewal and metastasis of CICs obtained from patients with colorectal cancer (CRC). Patients with elevated G9a were shown to face a high risk of relapse and poor survival rates. From a mechanistic perspective, G9a binds with and stabilizes RelB, thereby recruiting DNA methyltransferase 3 on the Let-7b promoter and repressing its expression. This leads to the activation of the K-RAS/β-catenin pathway and regulates self-renewal and function of CICs. These findings indicate that the G9a/RelB/Let-7b axis acts as a critical regulator in the maintenance of CIC phenotypes and is strongly associated with negative clinical outcomes. Thus, these findings may have diagnostic as well as therapeutic implications for the treatment of chemotherapy-resistant or metastatic CRC.

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Change history

  • 21 November 2016

    In this Article, we reported that G9a promotes colorectal-cancer-initiating cell self-renewal and function by repressing Let-7b expression in a manner independent of its enzymatic activity, thereby activating K-RAS and β-catenin signalling. However, it has come to our attention that during figure assembly certain images were inappropriately processed and duplicated in several figures of the article, including Figs 1d, 2d, 3b, 5a, 5f, 6h and 8f. In light of these errors and image reuse in multiple figures we have no confidence in the accuracy of the reported data, and the conclusions of the paper may be affected. Therefore, we wish to retract the paper. We deeply regret these circumstances and apologize to the scientific community.

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Acknowledgements

We thank C.-S. Chen (Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan) for the gift of K-RASG12D and K-RASG12V plasmid. We also thank the Technology Commons in the College of Life Science and Center for Systems Biology, National Taiwan University, for instrument support for cell sorting. This work was supported by grants from the National Science Council, Taiwan (NSC 099-2811-C-099-003; NSC 100-2811-C-099-003; NSC 102-2321-B-002-034), the Ministry of Science and Technology, Taiwan (MOST 104-231-B-002-006; MOST 104-2320-B-002-070-MY3; MOST 104-2911-I-002-302); and National Taiwan University (NTU 104-R7559-6; NTU 104R8952-1; NTU 104R7602).

Author information

Author notes

    • Cheng-Chi Chang
    •  & Chia-Yu Chu

    These authors contributed equally to this work.

Affiliations

  1. Center for Systems Biology, National Taiwan University, Taipei 100, Taiwan

    • Shih-Ting Cha
  2. Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan

    • Shih-Ting Cha
    •  & Chia-Yu Chu
  3. Department of Otolaryngology, National Taiwan University Hospital, Taipei 100, Taiwan

    • Ching-Ting Tan
  4. Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei 100, Taiwan

    • Cheng-Chi Chang
  5. Department of Dentistry, National Taiwan University Hospital, Taipei 100, Taiwan

    • Cheng-Chi Chang
  6. Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan

    • Wei-Jiunn Lee
  7. Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan

    • Been-Zen Lin
    •  & Ming-Tsan Lin
  8. Department of Medical Education & Bioethics, Graduate Institute of Medical Education & Bioethics, National Taiwan University College of Medicine, Taipei 100, Taiwan

    • Ming-Tsan Lin
  9. Institute of Biochemical Science, College of Life Science, National Taiwan University, Taipei 100, Taiwan

    • Min-Liang Kuo
  10. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    • Min-Liang Kuo

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Contributions

S.-T.C. and M.-L.K. conceived and designed the experiments. S.-T.C. analysed the data with the assistance of C.-T.T. and B.-Z.L. for the clinical data analysis. S.-T.C., M.-L.K. and C.-C.C. wrote the paper with assistance from C.-Y.C. W.-J.L. designed and carried out in vivo work and a portion of the plasmid construction. The sample collection and treatment of CRC patients were performed by B.-Z.L. M.-T.L. carried out the sample collection and supervised this work. M.-L.K. designed and supervised this work.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ming-Tsan Lin or Min-Liang Kuo.

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DOI

https://doi.org/10.1038/ncb3395

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