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Downregulation of HINFP induces senescence-associated secretory phenotype to promote metastasis in a non-cell-autonomous manner in bladder cancer

Oncogene volume 41, pages 3587–3598 (2022)Cite this article

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Abstract

Transcription dysregulation is a salient characteristic of bladder cancer (BC), but no appropriate therapeutic target for it has been established. Here, we found that heterogeneous downregulation of histone H4 transcription factor (HINFP) was associated with senescence in BC tissues and that lower HINFP expression could predict an unfavorable outcome in BC patients. Knockout of HINFP transcriptionally inhibited H1F0 and H1FX to trigger DNA damage, consequently inducing cell senescence to repress the proliferation and growth of BC cells. However, the senescence-associated secretory phenotype, characterized by increases in MMP1/3, enhances the invasion and metastasis of non-senescent BC cells. Histone deacetylase inhibitors (HDACis) could efficiently eliminate the senescent cells induced by HINFP knockout to suppress the invasion and metastasis of BC cells. Our study suggests that HDACis, widely used in multiple cancer types in a clinical context, may also benefit BC patients with metastases induced by cell senescence.

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Fig. 1: HINFP is required for BC cell growth.
Fig. 2: Knockout of HINFP induces senescence in BC cells by transcriptionally regulating H1F0 and H1FX.
Fig. 3: Downregulation of HINFP was associated with senescence in BC tissues, and lower expression of HINFP predicted an unfavorable prognosis in BC patients.
Fig. 4: Knockout of HINFP activates the SASP (MMPs) in BC cells via H1F0 and H1FX.
Fig. 5: HINFP-KO promotes the invasion and metastasis of BC cells in a non-cell-autonomous manner.
Fig. 6: Clearance of HINFP-KO-induced senescent cells by HDACis suppresses the invasion and metastasis of BC cells.
Fig. 7: The model proposed in this study.

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Data availability

The RNA-Seq data were deposited in the Genome Sequence Archive for Humans with accession code HRA001354. Other data used for the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Meisongzhu Yang from SYSUCC for her help in constructing the animal models and Dr. Jietian Jin from SYSUCC for help with pathological diagnosis. This work was supported by grants from the National Key Research and Development Program of China (2021YFA1300601 to TK, 2020YFA0509400 to JP), the National Nature Science Foundation of China (NSFC) (82030090 to TK, 82073103 to ZWL, 82103264 to XCZ, 82172939 to YW, 82002917 to LWZ), and the Science and Technology Program of Guangzhou (202002020092).

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  1. These authors contributed equally: Xianchong Zheng, Zefu Liu.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    Xianchong Zheng, Zefu Liu, Jianliang Zhong, Liwen Zhou, Jiawei Chen, Lisi Zheng, Ruhua Zhang, Yuanzhong Wu, Zhuowei Liu & Tiebang Kang

  2. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Xianchong Zheng, Zefu Liu, Jiawei Chen, Zhiyong Li & Zhuowei Liu

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

    Jingxuan Pan

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Contributions

XZ, YW, ZWL, and TK conceived the project, designed the experiments, and wrote the manuscript. XZ assisted by YW and ZFL performed most of the experiments and analyzed the data. ZL provided BC samples. JZ, LWZ, CJ, LSZ, RZ, and JP assisted with the experiments and provided technical assistance. All authors have read and approved the final version of the manuscript.

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Correspondence to Yuanzhong Wu, Zhuowei Liu or Tiebang Kang.

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Zheng, X., Liu, Z., Zhong, J. et al. Downregulation of HINFP induces senescence-associated secretory phenotype to promote metastasis in a non-cell-autonomous manner in bladder cancer. Oncogene 41, 3587–3598 (2022). https://doi.org/10.1038/s41388-022-02371-1

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