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
Share this article
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
  2. Download BibTeX
  3. Download .RIS

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).

Reviewing Editor

  1. Caigang Liu, Shengjing Hospital of China Medical University, China

Publication history

  1. Received: December 30, 2020
  2. Accepted: April 22, 2021
  3. Accepted Manuscript published: April 23, 2021 (version 1)
  4. Version of Record published: May 6, 2021 (version 2)

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.

Metrics

  • 1,590
    Page views
  • 228
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Cancer Biology

    Transferred mitochondria accumulate reactive oxygen species, promoting proliferation

    Chelsea U Kidwell, Joseph R Casalini ... Minna Roh-Johnson
    Research Article Updated

    Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.

    1. Cancer Biology
    2. Computational and Systems Biology

    Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE

    Matthew Roberts, Julia Ogden ... Carlos Lopez-Garcia
    Tools and Resources Updated

    Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.

    1. Biochemistry and Chemical Biology
    2. Cancer Biology

    Multi-targeted therapy resistance via drug-induced secretome fucosylation

    Mark Borris D Aldonza, Junghwa Cha ... Yoosik Kim
    Research Article

    Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.