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ΔNp63α exerts antitumor functions in cervical squamous cell carcinoma

Oncogene volume 39, pages 905–921 (2020)Cite this article

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Abstract

The molecular basis underlying the aggressive nature and excessive proliferation of cervical squamous cancer cell remains unclear. ΔNp63α is the predominant isotype of p63 expressed in the epithelia and regulates epithelial cell differentiation. The pro-/anti-tumor role of ΔNp63α in different kinds of solid tumors remains controversial and the precise molecular mechanisms are still elusive. In this study, we uncovered the molecular functions of ΔNp63α in cervical squamous cell carcinoma to clarify its roles as a tumor suppressor. We demonstrated that ΔNp63α suppressed cell migration, invasiveness, and tumor growth in SiHa and ME-180 cells with both in vivo and in vitro assays. Mechanistic investigation via RNA-sequencing and chromatin immunoprecipitation-sequencing revealed that ΔNp63α exerted its antitumor capacity via regulating the expression of a cohort of cell junction genes. Further, we showed that ZNF385B and CLDN1 were two direct ΔNp63α targets with significant relevance to cervical squamous cell carcinoma examined in cell cultures, tumor xenografts, and clinic tumors. We also demonstrated that ΔNp63α downregulated NFATC1 to reduce cisplatin resistance. These findings shed new lights on functions of ΔNp63α in tumors and providing novel insights in targeted therapy of cervical cancers.

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Data availability

The accession number for the RNA-seq and ChIP-seq data reported in this paper is GEO: GSE135257.

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Acknowledgements

We would like to thank Yuhui Miao, Huimin Liu, Lu Qi, Xu Liu, Shuai Wei, Jingxin Li in University of Science and Technology of China for their valuable comments during the preparation of the manuscript. This work was supported by the National Natural Science Foundation of China (No. 81872110, 31600657, 81272881, 8137277"9, 81372777, 31725016, and 81902632); National Key Research and Development Program (2018YFC1003903); Anhui Provincial Key Research and Development Projects (1704a0802151); the Strategic Priority Research Program (Pilot study): “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (grant XDPB10).

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Author notes

  1. These authors contributed equally: Ying Zhou, Hanyuan Liu

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science & Technology of China, Anhui Provincial Hospital, Hefei, 230001, Anhui Province, China

    Ying Zhou, Lili Qian, Dabao Wu, Zhen Shen & Liang Chen

  2. Anhui Medical University, Hefei, 230001, Anhui Province, China

    Hanyuan Liu, Juan Wang, Fei Xu & Weiguo Song

  3. Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, 230027, Hefei, China

    Xiaolin Wang, Weihua Xiao, Ge Shan & Liang Chen

  4. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, 100730, Beijing, China

    Dingqing Feng & Bin Ling

  5. CAS Centre for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, CAS, 200031, Shanghai, China

    Ge Shan

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Contributions

Y.Z., G.S., X.L.W. and L.C. conceived the idea, designed the experiments, analyzed the data, wrote the paper with input from all authors and oversaw the project. F.X., L.L.Q. and J.W. performed the in vivo experiments. J.W., X.L.W. and F.X. performed the ChIP-seq, RNA-seq, qRT-PCR and analysis of the results. W.G.S. and D.Q.F. constructed the plasmids and established the stable cells. H.Y.L., Z.S., D.B.W. and B.L. performed IHC. H.Y.L. carried out most of the revision experiments. Y.Z., G.S. and L.C. wrote, reviewed, and/or revised the manuscript.

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Correspondence to Ge Shan or Liang Chen.

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Significance: ΔNp63α functions as a tumor suppressor in CSCC by regulating the expression of a cohort of cell junction genes and some other target genes such as CLDN1, ZNF385B, and NFATC1.

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Zhou, Y., Liu, H., Wang, J. et al. ΔNp63α exerts antitumor functions in cervical squamous cell carcinoma. Oncogene 39, 905–921 (2020). https://doi.org/10.1038/s41388-019-1033-x

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