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MORC4 plays a tumor-promoting role in colorectal cancer via regulating PCGF1/CDKN1A axis in vitro and in vivo

Cancer Gene Therapy volumeĀ 30,Ā pages 985ā€“996 (2023)Cite this article

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Abstract

MORC family CW-type zinc finger 4 (MORC4) possessing nuclear matrix binding domains has been observed to be involved in multiple cancer development. By digging three gene expression omnibus (GEO) gene microarrays (GSE110223, GSE110224 and GSE24514), we found that MORC4 was overexpressed in colorectal cancer (CRC) samples (log2 Fold change >1, pā€‰<ā€‰0.05). We aimed to investigate the role of MORC4 in CRC malignant behaviors, with an emphasis on polycomb group ring finger 1 (PCGF1)/cyclin-dependent kinase inhibitor 1A (CDKN1A) axis. Firstly, we confirmed MORC4 as an upregulated gene in 60 pairs of frozen CRC and adjacent normal samples. MORC4 overexpression increased proliferation and metastasis, and decreased apoptosis in SW480 and HT29 cells, which was diminished by the knockdown of PCGF1, a transcriptional repressor of CDKN1A (a potent cyclin-dependent kinase inhibitor). MORC4 was further identified as a novel molecule that interacted with PCGF1 via coimmunoprecipitation. MORC4 itself did not substantially suppress CDKN1A transcriptional activity, but it augmented PCGF1ā€™s effect on CDKN1A. Additionally, MORC4 acted as the substrate of HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) and was degraded through ubiquitin-proteasome system. Collectively, our work suggested that MORC4 accelerated CRC progression via governing PCGF1/CDKN1A signaling.

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Fig. 1: MORC4 expression in Clinical CRC samples.
Fig. 2: MORC4 expression in CRC cell lines.
Fig. 3: The pro-proliferative role of MORC4 in CRC cells.
Fig. 4: The pro-metastatic role of MORC4 in CRC cells.
Fig. 5: The anti-growth effect induced by MORC4 silencing in vivo.
Fig. 6: MORC4 regulated CRC malignant behaviors via PCGF1/CDKN1A signaling.
Fig. 7: E3 ubiquitin ligase HECW2 mediated MORC4 proteasomal degradation.
Fig. 8: The schematic diagram of this work.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the experimental platform of Shengjing Hospital of China Medical University.

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Authors and Affiliations

  1. Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China

    Yichao Liang,Ā Di Wu,Ā Qiao Qu,Ā Zhilong LiĀ &Ā Hongzhuan Yin

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  1. Yichao Liang
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YL designed, wrote, and edited the manuscript. DW and QQ conducted experiments. ZL completed the data analysis. HY directed the study, wrote, and edited the manuscript.

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Correspondence to Hongzhuan Yin.

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Liang, Y., Wu, D., Qu, Q. et al. MORC4 plays a tumor-promoting role in colorectal cancer via regulating PCGF1/CDKN1A axis in vitro and in vivo. Cancer Gene Ther 30, 985ā€“996 (2023). https://doi.org/10.1038/s41417-023-00605-2

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