1. Cancer Biology

Post-transcriptional repression of circadian component CLOCK regulates cancer-stemness in murine breast cancer cells

  1. Takashi Ogino
  2. Naoya Matsunaga
  3. Takahiro Tanaka
  4. Tomohito Tanihara
  5. Hideki Terajima
  6. Hikari Yoshitane
  7. Yoshitaka Fukada
  8. Akito Tsuruta
  9. Satoru Koyanagi
  10. Shigehiro Ohdo  Is a corresponding author
  1. Kyushu University, Japan
  2. The University of Tokyo, Japan
https://doi.org/10.7554/eLife.66155
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Cite this article
  1. Takashi Ogino
  2. Naoya Matsunaga
  3. Takahiro Tanaka
  4. Tomohito Tanihara
  5. Hideki Terajima
  6. Hikari Yoshitane
  7. Yoshitaka Fukada
  8. Akito Tsuruta
  9. Satoru Koyanagi
  10. Shigehiro Ohdo
(2021)
Post-transcriptional repression of circadian component CLOCK regulates cancer-stemness in murine breast cancer cells
eLife 10:e66155.
https://doi.org/10.7554/eLife.66155
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Abstract

Disruption of the circadian clock machinery in cancer cells is implicated in tumor malignancy. Studies on cancer therapy reveal the presence of heterogeneous cells, including breast cancer stem-like cells (BCSCs), in breast tumors. BCSCs are often characterized by high aldehyde dehydrogenase (ALDH) activity, associated with the malignancy of cancers. In this study, we demonstrated the negative regulation of ALDH activity by the major circadian component CLOCK in murine breast cancer 4T1 cells. The expression of CLOCK was repressed in high-ALDH-activity 4T1, and enhancement of CLOCK expression abrogated their stemness properties, such as tumorigenicity and invasive potential. Furthermore, reduced expression of CLOCK in high-ALDH-activity 4T1 was post-transcriptionally regulated by microRNA: miR-182. Knockout of miR-182 restored the expression of CLOCK, resulted in preventing tumor growth. Our findings suggest that increased expression of CLOCK in BCSCs by targeting post-transcriptional regulation overcame stemness-related malignancy and may be a novel strategy for breast cancer treatments.

Data availability

The full data of microarray analysis have been deposited in National Center for Biotechnology Information gene expression omnibus (miRNA microarray, Accession#:GSE157655; mRNA microarray, Accession#:GSE103598). All data generated or analysed during this study are included in the manuscript and supporting files. Source data files of the quantitative data have been provided for all figures.

The following previously published data sets were used

Article and author information

Author details

  1. Takashi Ogino

    Pharmaceutics, Kyushu University, Higashi-ku, Japan
    Competing interests
    The authors declare that no competing interests exist.

  2. Naoya Matsunaga

    Glocal Healthcare Science, Kyushu University, Higashi-ku, Japan
    Competing interests
    The authors declare that no competing interests exist.

  3. Takahiro Tanaka

    Pharmaceutics, Kyushu University, Higashi-ku, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Tomohito Tanihara

    Pharmaceutics, Kyushu University, Higashi-ku, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Hideki Terajima

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  6. Hikari Yoshitane

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6319-3354

  7. Yoshitaka Fukada

    Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  8. Akito Tsuruta

    Pharmaceutics, Kyushu University, Higashi-ku, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Satoru Koyanagi

    Glocal Healthcare Science, Kyushu University, Higashi-ku, Japan
    Competing interests
    The authors declare that no competing interests exist.

  10. Shigehiro Ohdo

    Pharmaceutics, Kyushu University, Higashi-ku, Japan
    For correspondence
    ohdo@phar.kyushu-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4795-9764

Funding

Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research A,16H02636)

  • Shigehiro Ohdo

Japan Agency for Medical Research and Development (JP20am0101091)

  • Shigehiro Ohdo

Japan Agency for Medical Research and Development (JP21am0101091)

  • Shigehiro Ohdo

Ministry of Education, Culture, Sports, Science and Technology (Challenging Exploratory Research,17H06262)

  • Shigehiro Ohdo

Ministry of Education, Culture, Sports, Science and Technology (Challenging Exploratory Research,20K21484)

  • Satoru Koyanagi

Ministry of Education, Culture, Sports, Science and Technology (Challenging Exploratory Research,20K21901)

  • Naoya Matsunaga

Ministry of Education, Culture, Sports, Science and Technology (Scientific Research B,18H03192)

  • Naoya Matsunaga

Ministry of Education, Culture, Sports, Science and Technology (Specially Promoted Research,17H06096)

  • Yoshitaka Fukada

Ministry of Education, Culture, Sports, Science and Technology (Scientific Research B,25440041)

  • Hikari Yoshitane

Japan Agency for Medical Research and Development (PRIME,17937210)

  • Hikari Yoshitane

Ministry of Education, Culture, Sports, Science and Technology (JSPS KAKENHI Grant,17J01969)

  • Takashi Ogino

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures were performed after approval and following the guidelines of Kyushu University (approval number: A20-131-0).

Copyright

© 2021, Ogino et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Takashi Ogino
  2. Naoya Matsunaga
  3. Takahiro Tanaka
  4. Tomohito Tanihara
  5. Hideki Terajima
  6. Hikari Yoshitane
  7. Yoshitaka Fukada
  8. Akito Tsuruta
  9. Satoru Koyanagi
  10. Shigehiro Ohdo
(2021)
Post-transcriptional repression of circadian component CLOCK regulates cancer-stemness in murine breast cancer cells
eLife 10:e66155.
https://doi.org/10.7554/eLife.66155

Share this article

https://doi.org/10.7554/eLife.66155

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