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C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis

Oncogene volume 42, pages 1333–1346 (2023)Cite this article

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Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors in the gastrointestinal tract, and has been attracted a great deal attention and extensive investigation due to its high morbidity and mortality rates. The C4orf19 gene encodes a protein with uncharacterized function. Our preliminary exploration of the TCGA database indicated that C4orf19 is markedly downregulated in CRC tissues in comparison to that observed in normal colonic tissues, suggesting its potential association with CRC behaviors. Further studies showed a significant positive correlation between C4orf19 expression levels and CRC patient prognosis. Ectopic expression of C4orf19 inhibited the growth of CRC cells in vitro and tumorigenic ability in vivo. Mechanistic studies showed that C4orf19 binds to Keap1 at near the Lys615, which prevents the ubiquitination of Keap1 by TRIM25, thus protecting the Keap1 protein from degradation. The accumulated Keap1 results in USP17 degradation and in turn leading to the degradation of Elk-1, further attenuates its regulated CDK6 mRNA transcription and protein expression, as well as its mediated proliferation of CRC cells. Collectively, the present studies characterize function of C4orf19 as a tumor suppressor for CRC cell proliferation by targeting Keap1/USP17/Elk-1/CDK6 axis.

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Fig. 1: Expression of C4orf19 in CRC and correlation with patient prognosis.
Fig. 2: Effect of C4orf19 levels on CRC cell growth in vitro and in vivo.
Fig. 3: CDK6 is an effector of C4orf19 to inhibit CRC cell cycle progression.
Fig. 4: Overexpression of C4orf19 represses CDK6 transcription and downregulates Elk-1.
Fig. 5: C4orf19 decreases Elk-1 protein stability by downregulating USP17.
Fig. 6: USP17 is a novel ubiquitinated substrate of Keap1 in CRC cells.
Fig. 7: Keap1 is a direct target of C4orf19 and its protein half-life is affected by C4orf19.

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All data created and analyzed during this current work are involved in this published paper (and its supplementary information files).

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Acknowledgements

This work was partially supported by grants from the Natural Science Foundation of China (NSFC81601849), Zhejiang Provincial Medicine and Health Technology Project (2019RC217), the Natural Science Foundation of Zhejiang province (LY22H160005).

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Authors and Affiliations

  1. Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China

    Shirui Huang, Jizhen Li & Qipeng Xie

  2. Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Shuang Wu, Zhijian Zheng, Cong Wang, Hongyan Li, Lingling Zhao, Haishan Huang & Chuanshu Huang

  3. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Xiaodong Zhang

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Contributions

SH, QX, and CH conceived and designed the study. SH, JL, and SW detected the biological functions of cells, performed the RT-qPCR assays and the IHC staining assays, and conducted the statistical analyses. JL and SW performed the animal experiments. SH, ZZ, CW, HL, and XZ collected and analyzed clinical samples. SH, QX, HH and CH drafted the paper. All authors read and approved the final version of the paper.

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Correspondence to Qipeng Xie.

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All experiments related to clinical specimens were approved by the Ethics Committee of Wenzhou Medical University. All animal experiments were conducted in accordance with the regulations of the Experimental Center of Wenzhou Medical University. The regulations of the Experimental Animal Ethics Committee of Wenzhou Medical University.

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Huang, S., Li, J., Wu, S. et al. C4orf19 inhibits colorectal cancer cell proliferation by competitively binding to Keap1 with TRIM25 via the USP17/Elk-1/CDK6 axis. Oncogene 42, 1333–1346 (2023). https://doi.org/10.1038/s41388-023-02656-z

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