Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS

Nanamiya,Tomoyuki; Takane,Kiyoko; Yamaguchi,Kiyoshi; Okawara,Yuya; Arakawa,Mariko; Saku,Akari; Ikenoue,Tsuneo; Fujiyuki,Tomoko; Yoneda,Misako; Kai,Chieko; Furukawa,Yoichi

doi:10.3892/or.2023.8676

Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS

Authors:
- Tomoyuki Nanamiya
- Kiyoko Takane
- Kiyoshi Yamaguchi
- Yuya Okawara
- Mariko Arakawa
- Akari Saku
- Tsuneo Ikenoue
- Tomoko Fujiyuki
- Misako Yoneda
- Chieko Kai
- Yoichi Furukawa
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Affiliations: Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108‑8639, Japan, Division of Virus Engineering, Institute of Industrial Science, The University of Tokyo, Tokyo 153‑8505, Japan, Division of Virological Medicine, Institute of Industrial Science, The University of Tokyo, Tokyo 153‑8505, Japan, Division of Infectious Disease Control Science, Institute of Industrial Science, The University of Tokyo, Tokyo 153‑8505, Japan
Published online on: December 5, 2023 https://doi.org/10.3892/or.2023.8676
Article Number: 17
Copyright: © Nanamiya et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

PVRL4 (or nectin‑4) is a promising therapeutic target since its upregulated expression is found in a wide range of human cancer types. Enfortumab vedotin, an antibody‑drug conjugate targeting PVRL4, is clinically used for the treatment of urothelial bladder cancer. In addition, rMV‑SLAMblind, a genetically engineered oncolytic measles virus, can infect cancer cells and induce apoptosis through interaction with PVRL4. Although PVRL4 transcript levels are elevated in breast, lung and ovarian cancer, the mechanisms of its upregulation have not yet been uncovered. To clarify the regulatory mechanisms of elevated PVRL4 expression in breast cancer cells, Assay for Transposase‑Accessible Chromatin‑sequencing and chromatin immunoprecipitation‑sequencing (ChIP‑seq) data were used to search for its regulatory regions. Using breast cancer cells, an enhancer region was ultimately identified. Additional analyses, including ChIP and reporter assays, demonstrated that FOS interacted with the PVRL4 enhancer region, and that alterations of the FOS‑binding motifs in the enhancer region decreased reporter activity. Consistent with these data, exogenous expression of FOS enhanced the reporter activity and PVRL4 expression in breast cancer cells. Furthermore, RNA‑seq analysis using breast cancer cells treated with PVRL4 small interfering RNA revealed its possible involvement in the cytokine response and immune system. These data suggested that FOS was involved, at least partly, in the regulation of PVRL4 expression in breast cancer cells, and that elevated PVRL4 expression may regulate the response of cancer cells to cytokines and the immune system.

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