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Korea Genome Organization (한국유전체학회)
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Knockdown of vps54 aggravates tamoxifen-induced cytotoxicity in fission yeast

  • Lee, Sol (Department of New Drug Development, Chungnam National University) ;
  • Nam, Miyoung (Department of New Drug Development, Chungnam National University) ;
  • Lee, Ah-Reum (Department of New Drug Development, Chungnam National University) ;
  • Baek, Seung-Tae (Department of New Drug Development, Chungnam National University) ;
  • Kim, Min Jung (Department of New Drug Development, Chungnam National University) ;
  • Kim, Ju Seong (Department of New Drug Development, Chungnam National University) ;
  • Kong, Andrew Hyunsoo (Morrissey College of Arts and Sciences, Boston College) ;
  • Lee, Minho (Department of Life Science, Dongguk University-Seoul) ;
  • Lee, Sook-Jeong (Department of Bioactive Material Science, Jeonbuk National University) ;
  • Kim, Seon-Young (Personalized Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB)) ;
  • Kim, Dong-Uk (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology(KRIBB)) ;
  • Hoe, Kwang-Lae (Department of New Drug Development, Chungnam National University)
  • Received : 2021.09.13
  • Accepted : 2021.10.15
  • Published : 2021.12.31
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Abstract

Tamoxifen (TAM) is an anticancer drug used to treat estrogen receptor (ER)-positive breast cancer. However, its ER-independent cytotoxic and antifungal activities have prompted debates on its mechanism of action. To achieve a better understanding of the ER-independent antifungal action mechanisms of TAM, we systematically identified TAM-sensitive genes through microarray screening of the heterozygous gene deletion library in fission yeast (Schizosaccharomyces pombe). Secondary confirmation was followed by a spotting assay, finally yielding 13 TAM-sensitive genes under the drug-induced haploinsufficient condition. For these 13 TAM-sensitive genes, we conducted a comparative analysis of their Gene Ontology (GO) 'biological process' terms identified from other genome-wide screenings of the budding yeast deletion library and the MCF7 breast cancer cell line. Several TAM-sensitive genes overlapped between the yeast strains and MCF7 in GO terms including 'cell cycle' (cdc2, rik1, pas1, and leo1), 'signaling' (sck2, oga1, and cki3), and 'vesicle-mediated transport' (SPCC126.08c, vps54, sec72, and tvp15), suggesting their roles in the ER-independent cytotoxic effects of TAM. We recently reported that the cki3 gene with the 'signaling' GO term was related to the ER-independent antifungal action mechanisms of TAM in yeast. In this study, we report that haploinsufficiency of the essential vps54 gene, which encodes the GARP complex subunit, significantly aggravated TAM sensitivity and led to an enlarged vesicle structure in comparison with the SP286 control strain. These results strongly suggest that the vesicle-mediated transport process might be another action mechanism of the ER-independent antifungal or cytotoxic effects of TAM.

Keywords

Acknowledgement

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (MSIT; NRF-2017M3A 9B5060880). In addition, the authors were supported by Chungnam National University and the Korea Research Institute of Bioscience and Biotechnology (KRIBB).

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