ORIGINAL RESEARCH article
Front. Oncol.
Sec. Molecular and Cellular Oncology
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1547899
This article is part of the Research TopicDNA Damage, Repair and Mutagenesis: Targeting Cancer’s Achilles HeelView all 8 articles
NEK4 SUPPRESSES CELL PROLIFERATION IN BT20 TRIPLE NEGATIVE BREAST CANCER CELLS BY DIMINISHING EXPRESSION OF CELL CYCLE GENES WHILE ITS DEPLETION MITIGATES PROLIFERATION IN OTHER CELL LINES
Provisionally accepted
- New Mexico State University, Las Cruces, United States
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NIMA-related kinase 4 (NEK4), a serine/threonine protein kinase, is involved in several cellular processes including the DNA damage response and mRNA splicing, and we identified it as a potential new drug target in triple negative breast cancer. We observed via live-cell imaging, that multiple NEK4 depleted cell lines proliferated slower than control cells, except the BT20 and MCF12A cell lines in which proliferation was stimulated with NEK4 depletion. We hypothesized that NEK4 regulates genes involved in cell proliferation in BT20 cells. NEK4 depleted BT20 cells were subjected to RNA-seq. Enrichment analysis revealed upregulation of genes involved in cell cycle, mitosis and G-protein coupled receptor (GPCR) ligand binding and downregulation of genes involved in mRNA splicing, consistent with previous reports. We used the STRING database to select a subset of cell cycle genes that were upregulated in NEK4 depleted cells. We assessed cell cycle distribution and found a decrease in the percentage of cells in G0/G1 and increase in G2/M, suggesting an enhanced proliferative phenotype in BT20 cells. NEK4 depletion did not consistently alter expression of p21, a putative target of NEK4, in the multiple cell lines examined. We explored the role of NEK4 in DNA repair and observed NEK4 depletion did not impact basal DNA damage levels, but did decrease γH2AX foci following exposure to etoposide.Our data indicates that NEK4 depletion differentially alters cell proliferation in varying cell lines, most likely via altering cell cycle regulation. Understanding its role in cell cycle regulation could be valuable in developing therapeutic strategies and patient stratification, as we and others have identified NEK4 as a potential target for new drug development in triple negative breast cancer.
Keywords: NEK4, proliferation, Cell Cycle, DNA Repair, p21
Received: 18 Dec 2024; Accepted: 31 Jul 2025.
Copyright: © 2025 JOSHI, SEPULVEDA, LUJAN, DEVARGAS and ASHLEY. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: AMANDA K ASHLEY, New Mexico State University, Las Cruces, United States
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