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

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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, p < 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 PCGF1’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.

References

  1. Thanikachalam K, Khan G. Colorectal cancer and nutrition. Nutrients 2019;11:164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shapiro JA, Soman AV, Berkowitz Z, Fedewa SA, Sabatino SA, De Moor JS, et al. Screening for colorectal cancer in the United States: Correlates and time trends by type of test. Cancer Epidemiol Biomark Prev. 2021;30:1554–65.

    Article  Google Scholar 

  3. Cheng L, Eng C, Nieman LZ, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol Cancer Clin Trials. 2011;34:573–80.

    Google Scholar 

  4. Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: Systematic review and meta-analysis. Ann Intern Med. 2014;160:171–81.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  PubMed  Google Scholar 

  6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  PubMed  Google Scholar 

  7. Bailey CE, Hu CY, You YN, Bednarski BK, Rodriguez-Bigas MA, Skibber JM, et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975-2010. JAMA Surg. 2015;150:17–22.

    Article  PubMed  PubMed Central  Google Scholar 

  8. The Lancet Oncology. Colorectal cancer: a disease of the young? Lancet Oncol. 2017;18:413.

    Article  PubMed  Google Scholar 

  9. Hong G, Qiu H, Wang C, Jadhav G, Wang H, Tickner J, et al. The emerging role of MORC family proteins in cancer development and bone homeostasis. J Cell Physiol. 2017;232:928–34.

    Article  CAS  PubMed  Google Scholar 

  10. Li DQ, Nair SS, Kumar R. The MORC family: New epigenetic regulators of transcription and DNA damage response. Epigenetics. 2013;8:685–93. https://doi.org/10.4161/epi.24976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Söderman J, Norén E, Christiansson M, Bragde H, Thiébaut R, Hugot JP, et al. Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease. World J Gastroenterol. 2013;19:4935–43.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Weiss FU, Hesselbarth N, Párniczky A, Mosztbacher D, Lämmerhirt F, Ruffert C, et al. Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis. Pancreatology 2018;18:477–81.

    Article  CAS  PubMed  Google Scholar 

  13. Norén E, Verma D, Söderkvist P, Weisselberg T, Söderman J, Lotfi K, et al. Single nucleotide polymorphisms in MORC4, CD14, and TLR4 are related to outcome of allogeneic stem cell transplantation. Ann Transpl. 2016;21:56–67.

    Article  Google Scholar 

  14. Liggins AP, Cooper CDO, Lawrie CH, Brown PJ, Collins GP, Hatton CS, et al. MORC4, a novel member of the MORC family, is highly expressed in a subset of diffuse large B-cell lymphomas. Br J Haematol. 2007;138:479–86.

    Article  CAS  PubMed  Google Scholar 

  15. Yang Z, Zhuang Q, Hu G, Geng S. MORC4 is a novel breast cancer oncogene regulated by miR-193b-3p. J Cell Biochem. 2019;120:4634–43.

    Article  CAS  PubMed  Google Scholar 

  16. Luo J, Zeng S, Tian C. Morc4 promotes chemoresistance of luminal a/b breast cancer via stat3-mediated mid2 upregulation. Onco Targets Ther. 2020;13:6795–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Duan X, Guo G, Pei X, Wang X, Li L, Xiong Y, et al. Baicalin inhibits cell viability, migration and invasion in breast cancer by regulating mir-338-3p and MORC4. Onco Targets Ther. 2019;12:11183–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ji G, Zhou W, Du J, Zhou J, Wu D, Zhao M, et al. PCGF1 promotes epigenetic activation of stemness markers and colorectal cancer stem cell enrichment. Cell Death Dis. 2021;12:633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang P, Zhang Y, Mao L, Zhang Z, Chen W. Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Lett. 2009;277:227–34.

    Article  CAS  PubMed  Google Scholar 

  20. Gong Y, Yue J, Wu X, Wang X, Wen J, Lu L, et al. NSPc1 is a cell growth regulator that acts as a transcriptional repressor of p21Waf1/Cip1 via the RARE element. Nucleic Acids Res. 2006;34:6158–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yoo BH, Wu X, Li Y, Haniff M, Sasazuki T, Shirasawa S, et al. Oncogenic ras-induced down-regulation of autophagy mediator Beclin-1 is required for malignant transformation of intestinal epithelial cells. J Biol Chem. 2010;285:5438–49.

    Article  CAS  PubMed  Google Scholar 

  22. Tang X, Wang H, Fan L, Wu X, Xin A, Ren H, et al. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med. 2011;50:1599–609.

    Article  CAS  PubMed  Google Scholar 

  23. Wang C, Liu H, Yang M, Bai Y, Ren H, Zou Y, et al. RNA-Seq based transcriptome analysis of endothelial differentiation of bone marrow mesenchymal stem cells. Eur J Vasc Endovasc Surg 2020;59:834–42.

    Article  PubMed  Google Scholar 

  24. Wang H, Zhang L, Luo Q, Liu J, Wang G. MORC protein family-related signature within human disease and cancer. Cell Death Dis. 2021;12:1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Condomines M, Hose D, Raynaud P, Hundemer M, De Vos J, Baudard M, et al. Cancer/Testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis. J Immunol. 2007;178:3307–15.

    Article  CAS  PubMed  Google Scholar 

  26. Pan Z, Ding Q, Guo Q, Guo Y, Wu L, Wu L, et al. MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance. Int J Oncol. 2018;53:59–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu J, Zhang Q, Ruan B, Chen W, Zheng J, Xu B, et al. MORC2 regulates C/EBPα-mediated cell differentiation via sumoylation. Cell Death Differ. 2019;26:1905–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dukers DF, Van Galen JC, Giroth C, Jansen P, Sewalt RGAB, Otte AP, et al. Unique polycomb gene expression pattern in Hodgkin’s Lymphoma and Hodgkin’s lymphoma-derived cell lines. Am J Pathol. 2004;164:873–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yan R, Cui F, Dong L, Liu Y, Chen X, Fan R. Repression of PCGF1 decreases the proliferation of glioblastoma cells in association with inactivation of c-Myc signaling pathway. Onco Targets Ther. 2020;13:253–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Oliviero G, Munawar N, Watson A, Streubel G, Manning G, Bardwell V, et al. The variant Polycomb Repressor Complex 1 component PCGF1 interacts with a pluripotency sub-network that includes DPPA4, a regulator of embryogenesis. Sci Rep. 2015;5:18388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu PS, Xia QS, Wu F, Li DK, Qi YJ, Hu Y, et al. NSPc1 promotes cancer stem cell self-renewal by repressing the synthesis of all-trans retinoic acid via targeting RDH16 in malignant glioma. Oncogene 2017;36:4706–18.

    Article  CAS  PubMed  Google Scholar 

  32. Gong Y, Wang X, Liu J, Shi L, Yin B, Peng X, et al. NSPc1, a mainly nuclear-localized protein of novel PcG family members, has a transcription repression activity related to its PKC phosphorylation site at S183. FEBS Lett. 2005;579:115–21.

    Article  CAS  PubMed  Google Scholar 

  33. Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 2005;30:630–41.

    Article  CAS  PubMed  Google Scholar 

  34. Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair. 2016;42:63–71.

    Article  CAS  PubMed  Google Scholar 

  35. Cao N, Yu Y, Zhu H, Chen M, Chen P, Zhuo M, et al. SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression. Cell Death Dis. 2020;11:351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ji H, Hui B, Wang J, Zhu Y, Tang L, Peng P, et al. Wang, Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer proliferation by partly silencing p21 expression. Cancer Sci. 2019;110:72–85.

    Article  CAS  PubMed  Google Scholar 

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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, Di Wu, Qiao Qu, Zhilong Li & Hongzhuan Yin

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  1. Yichao Liang
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  2. Di Wu
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  3. Qiao Qu
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  4. Zhilong Li
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  5. Hongzhuan Yin
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Contributions

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, 985–996 (2023). https://doi.org/10.1038/s41417-023-00605-2

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