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Cell division cycle 7 is a potential therapeutic target in oral squamous cell carcinoma and is regulated by E2F1

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Abstract

Cell division cycle 7 (Cdc7) plays important roles in the regulation of the initiation of DNA replication throughout S phase. Whether inhibition of Cdc7 has a direct antitumour effect in oral squamous cell carcinoma (OSCC) remains unclear. In this study, XL413, a novel Cdc7 inhibitor, markedly inhibited the viability of OSCC cells but not that of non-tumour primary cells. There was a synergistic effect between XL413 and DNA-damaging agents (e.g. cisplatin and 5-fluorouracil) on OSCC in vitro and in vivo. Moreover, XL413 exhibited a notable antitumour effect on OSCC patients with high Cdc7 expression in mini patient-derived xenografts model. The proliferation was significantly inhibited in OSCC cells after Cdc7 silencing. Cdc7 knockdown significantly induced apoptosis in OSCC cell lines. Furthermore, we demonstrated that Cdc7 was overexpressed and transcriptionally regulated by E2F1 in OSCC by using chromatin immunoprecipitation and luciferase assays. Our results reveal that XL413 has an excellent antitumour effect in OSCC. Importantly, it does not inhibit the proliferation of non-tumour cells. These findings suggest that the overexpression of Cdc7 promotes progression in OSCC and that inhibition of Cdc7 is a very promising therapy for OSCC patients.

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Funding

This study was supported by the National Natural Science Foundation of China (No.81430012), by research grant BXJ201728 from Shanghai Jiao Tong University School of Medicine.

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Authors and Affiliations

  1. Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China

    Shufang Jin, Hailong Ma, Wenyi Yang, Houyu Ju & Zhiyuan Zhang

  2. Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, 200011, China

    Shufang Jin, Hailong Ma, Wenyi Yang, Houyu Ju & Zhiyuan Zhang

  3. Department of Oral Pathology, Shanghai Ninth People’s Hospital, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Lizhen Wang

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  1. Shufang Jin
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  4. Houyu Ju
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Correspondence to Zhiyuan Zhang.

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Shufang Jin and Hailong Ma shared first authorship.

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Supplementary Figure S1

XL413 exerts a synergistic antitumour effect with cisplatin and 5-fluorouracil. The cell viability of HN6 and Cal27 cell after treatment with XL413 (10 μM) combined with CDDP (0 to 1000 μM) or 5-Fu (0 to 10,000 μM) was detected by MTT assay (GIF 52 kb)

High-resolution image (TIFF 572 kb)

Supplementary Figure S2

Downregulation of Cdc7 expression by siRNA was confirmed by real-time PCR. (a) The mRNA of Cdc7 was detected after transfection with siRNA (#1, #2, #3) for 24 h in HN6 cells. (b) The mRNA of Cdc7 was detected after transfection with siRNA (#1, #2, #3) for 24 h in Cal27 cells (GIF 633 kb)

High-resolution image (TIFF 998 kb)

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Jin, S., Ma, H., Yang, W. et al. Cell division cycle 7 is a potential therapeutic target in oral squamous cell carcinoma and is regulated by E2F1. J Mol Med 96, 513–525 (2018). https://doi.org/10.1007/s00109-018-1636-7

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  • DOI: https://doi.org/10.1007/s00109-018-1636-7

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