Post-transcriptional repression of circadian component CLOCK regulates cancer-stemness in murine breast cancer cells
- Kyushu University, Japan
- The University of Tokyo, Japan
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.
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ALDH high or low cell in 4T1 cellNCBI Gene Expression Omnibus, GSE103598.
Article and author information
Author details
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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