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Theranostics 2023; 13(3):873-895. doi:10.7150/thno.77444 This issue Cite

Research Paper

NQO1 regulates cell cycle progression at the G2/M phase

Eun-Taex Oh^1,#, Ha Gyeong Kim^2,#, Chul Hoon Kim³, Jeonghun Lee⁴, Chulhee Kim⁴, Jae-Seon Lee^2,5,6, Yunmi Cho², Heon Joo Park^2,6,7,✉

1. Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea
2. Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Republic of Korea
3. Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
4. Department of Polymer Science & Engineering, Inha University, Incheon 22212, Republic of Korea
5. Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea
6. Research Center for Controlling Intracellular Communication, College of Medicine, Inha University, Incheon 22212, Republic of Korea
7. Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of Korea
^#Eun-Taex Oh and Ha Gyeong Kim contributed equally to this work.

✉ Corresponding author: Heon Joo Park, MD, PhD., Department of Microbiology, Research Center for Controlling Intracellular Communication, Program in Biomedical Science & Engineering, College of Medicine, Inha University, Inha-ro 100, Michuhol-gu, Incheon 22212, Republic of Korea. Tel: +82-32-860-9800; Fax: +82-32-885-8302; E-mail: park001ac.kr More

Abstract

Rationale: Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is associated with tumor cell proliferation and growth in several human cancer types. However, the molecular mechanisms underlying the activity of NQO1 in cell cycle progression are currently unclear. Here, we report a novel function of NQO1 in modulation of the cell cycle regulator, cyclin-dependent kinase subunit-1 (CKS1), at the G2/M phase through effects on the stability of c‑Fos.

Methods: The roles of the NQO1/c-Fos/CKS1 signaling pathway in cell cycle progression were analyzed in cancer cells using synchronization of the cell cycle and flow cytometry. The mechanisms underlying NQO1/c-Fos/CKS1-mediated regulation of cell cycle progression in cancer cells were studied using siRNA approaches, overexpression systems, reporter assays, co-immunoprecipitation, pull-down assays, microarray analysis, and CDK1 kinase assays. In addition, publicly available data sets and immunohistochemistry were used to investigate the correlation between NQO1 expression levels and clinicopathological features in cancer patients.

Results: Our results suggest that NQO1 directly interacts with the unstructured DNA-binding domain of c-Fos, which has been implicated in cancer proliferation, differentiation, and development as well as patient survival, and inhibits its proteasome-mediated degradation, thereby inducing CKS1 expression and regulation of cell cycle progression at the G2/M phase. Notably, a NQO1 deficiency in human cancer cell lines led to suppression of c-Fos-mediated CKS1 expression and cell cycle progression. Consistent with this, high NQO1 expression was correlated with increased CKS1 and poor prognosis in cancer patients.

Conclusions: Collectively, our results support a novel regulatory role of NQO1 in the mechanism of cell cycle progression at the G2/M phase in cancer through effects on c‑Fos/CKS1 signaling.

Keywords: NQO1, cancer cell, cell cycle, c-Fos, CKS1

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