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VEZF1, destabilized by STUB1, affects cellular growth and metastasis of hepatocellular carcinoma by transcriptionally regulating PAQR4

Cancer Gene Therapy volume 30, pages 256–266 (2023)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is an aggressive solid malignancy, and recurrence and metastasis are major incentives contributing to its poor outcome. Vascular endothelial zinc finger 1 (VEZF1) has been recognized as an oncoprotein in certain types of cancer, but the expression pattern and regulatory mechanism in HCC remains unclear. This study focused on the functional effect and regulatory basis of VEZF1 in HCC. Microarray analysis identified the differentially expressed VEZF1 in HCC, and we validated its raised expression in HCC clinical samples. Artificial modulation of VEZF1 (knockdown and overexpression) was conducted to explore its role in HCC progression both in vitro and in vivo. It was shown that silencing of VEZF1 suppressed, whereas its overexpression promoted HCC cellular proliferation and metastasis abilities. Mechanistically, VEZF1 transcriptionally activated progestin and adipoQ receptor 4 (PAQR4) to accelerate HCC progression. Furthermore, VEZF1 is confirmed as a substrate of stress-inducible phosphoprotein 1 homology and U-box containing protein 1 (STUB1), and its stability is impacted by STUB1-mediated ubiquitination degradation. Conjointly, our work suggested that VEZF1, destabilized by STUB1, participates in HCC progression by regulating PAQR4. The STUB1/VEZF1/PAQR4 mechanism might provide novel insights on guiding early diagnosis and therapy in HCC patients.

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Fig. 1: VEZF1 is upregulated in human HCC.
Fig. 2: VEZF1 accelerates HCC cell proliferation in vitro.
Fig. 3: VEZF1 promotes HCC cell metastasis in vitro.
Fig. 4: VEZF1 facilitates tumor growth and metastasis in vivo.
Fig. 5: VEZF1 transcriptionally regulates PAQR4 to mediate proliferation and metastasis of HCC.
Fig. 6: U-box domain of STUB1 mediates the ubiquitination and degradation of VEZF1 protein.
Fig. 7: Schematic illustration for the mechanism of STUB1-mediated VEZF1 ubiquitination and subsequent PAQR4 transcriptional activation in HCC.

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References

  1. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  Google Scholar 

  2. Nault JC. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pr Res Clin Gastroenterol. 2014;28:937–47.

    Article  CAS  Google Scholar 

  3. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4–13.

    Article  CAS  Google Scholar 

  4. Dutta R, Mahato RI. Recent advances in hepatocellular carcinoma therapy. Pharm Ther. 2017;173:106–17.

    Article  CAS  Google Scholar 

  5. Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 2012;62:394–9.

    Article  Google Scholar 

  6. Clark SP, Lewis CD, Felsenfeld G. Properties of BGP1, a poly(dG)-binding protein from chicken erythrocytes. Nucleic Acids Res. 1990;18:5119–26.

    Article  CAS  Google Scholar 

  7. Miyashita H, Kanemura M, Yamazaki T, Abe M, Sato Y. Vascular endothelial zinc finger 1 is involved in the regulation of angiogenesis: Possible contribution of stathmin/OP18 as a downstream target gene. Arterioscler Thromb Vasc Biol. 2004;24:878–84.

    Article  CAS  Google Scholar 

  8. AlAbdi L, He M, Yang Q, Norvil AB, Gowher H. The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells. J Biol Chem. 2018;293:11109–18.

    Article  CAS  Google Scholar 

  9. Aitsebaomo J, Kingsley-Kallesen ML, Wu Y, Quertermous T, Patterson C. Vezf1/DB1 is an endothelial cell-specific transcription factor that regulates expression of the endothelin-1 promoter. J Biol Chem. 2001;276:39197–205.

    Article  CAS  Google Scholar 

  10. Gowher H, Brick K, Camerini-Otero RD, Felsenfeld G. Vezf1 protein binding sites genome-wide are associated with pausing of elongating RNA polymerase II. Proc Natl Acad Sci USA. 2012;109:2370–5.

    Article  CAS  Google Scholar 

  11. Paavola J, Alakoski T, Ulvila J, Kilpiö T, Sirén J, Perttunen S, et al. Vezf1 regulates cardiac structure and contractile function. EBioMedicine. 2020;51:102608.

    Article  Google Scholar 

  12. Kuhnert F, Campagnolo L, Xiong JW, Lemons D, Fitch MJ, Zou Z, et al. Dosage-dependent requirement for mouse Vezf1 in vascular system development. Dev Biol. 2005;283:140–56.

    Article  CAS  Google Scholar 

  13. Yin R, Guo L, Gu J, Li C, Zhang W. Over expressing miR-19b-1 suppress breast cancer growth by inhibiting tumor microenvironment induced angiogenesis. Int J Biochem Cell Biol. 2018;97:43–51.

    Article  CAS  Google Scholar 

  14. Benini S, Gamberi G, Cocchi S, Righi A, Frisoni T, Longhi A, et al. Identification of a novel fusion transcript EWSR1-VEZF1 by anchored multiplex PCR in malignant peripheral nerve sheath tumor. Pathol Res Pr. 2020;216:152760.

    Article  CAS  Google Scholar 

  15. Asmamaw MD, Liu Y, Zheng YC, Shi XJ, Liu HM. Skp2 in the ubiquitin-proteasome system: A comprehensive review. Med Res Rev. 2020;40:1920–49.

    Article  CAS  Google Scholar 

  16. Narayanan S, Cai CY, Assaraf YG, Guo HQ, Cui Q, Wei L, et al. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist Updat. 2020;48:100663.

    Article  Google Scholar 

  17. Hyer ML, Milhollen MA, Ciavarri J, Fleming P, Traore T, Sappal D, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med. 2018;24:186–93.

    Article  CAS  Google Scholar 

  18. Meacham GC, Patterson C, Zhang W, Younger JM, Cyr DM. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol. 2001;3:100–5.

    Article  CAS  Google Scholar 

  19. Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity. 2013;39:272–85.

    Article  CAS  Google Scholar 

  20. Wang S, Li Y, Hu YH, Song R, Gao Y, Liu HY, et al. STUB1 is essential for T-cell activation by ubiquitinating CARMA1. Eur J Immunol. 2013;43:1034–41.

    Article  CAS  Google Scholar 

  21. Shang Y, Zhao X, Tian B, Wang Y, Ren F, Jia B, et al. CHIP/Stub1 interacts with eIF5A and mediates its degradation. Cell Signal. 2014;26:1098–104.

    Article  CAS  Google Scholar 

  22. Tang DE, Dai Y, Lin LW, Xu Y, Liu DZ, Hong XP, et al. STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling. Cancer Sci. 2019;110:3145–56.

    Article  CAS  Google Scholar 

  23. Liu CM, Yu CC, Lin T, Liao YW, Hsieh PL, Yu CH, et al. E3 ligase STUB1 attenuates stemness and tumorigenicity of oral carcinoma cells via transglutaminase 2 regulation. J Formos Med Assoc. 2020;119:1532–8.

    Article  CAS  Google Scholar 

  24. Wang Y, Ren F, Wang Y, Feng Y, Wang D, Jia B, et al. CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer. Carcinogenesis. 2014;35:983–91.

    Article  Google Scholar 

  25. Liu B, Li X, Sun F, Tong X, Bai Y, Jin K, et al. HP-CagA+ regulates the expression of CDK4/CyclinD1 via reg3 to change cell cycle and promote cell proliferation. Int J Mol Sci. 2019;21:224.

  26. Yan KX, Liu BC, Shi XL, You BR, Xu M. Role of cyclinD1 and CDK4 in the carcinogenesis induced by silica. Biomed Environ Sci. 2005;18:286–96.

    CAS  Google Scholar 

  27. Yang Y, Li X, Du J, Yin Y, Li Y. Involvement of microRNAs-MMPs-E-cadherin in the migration and invasion of gastric cancer cells infected with Helicobacter pylori. Exp Cell Res. 2018;367:196–204.

    Article  CAS  Google Scholar 

  28. Curran S, Murray GI. Matrix metalloproteinases: Molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer. 2000;36:1621–30.

    Article  CAS  Google Scholar 

  29. Jennbacken K, Tesan T, Wang W, Gustavsson H, Damber JE, Welén K. N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer. Endocr Relat Cancer. 2010;17:469–79.

    Article  CAS  Google Scholar 

  30. Gerald D, Adini I, Shechter S, Perruzzi C, Varnau J, Hopkins B, et al. RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription. Nat Commun. 2013;4:2824.

    Article  Google Scholar 

  31. Zhao G, Shi X, Sun Z, Zhao P, Lu Z. PAQR4 promotes the development of hepatocellular carcinoma by activating PI3K/AKT pathway. Acta Biochim Biophys Sin. 2021;53:1602–13.

    Article  CAS  Google Scholar 

  32. Ali A, Kumar V, Banerjea AC. STUB1/CHIP promotes ubiquitination and degradation of HIV-1 Vif to restore the cellular level of APOBEC3G protein. Biochem Biophys Res Commun. 2021;574:27–32.

    Article  CAS  Google Scholar 

  33. Shi Y, Wang X, Xu Z, He Y, Guo C, He L, et al. PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells. J Biol Chem. 2020;295:13798–811.

    Article  CAS  Google Scholar 

  34. Wang W, Zhou Z, Xiang L, Lv M, Ni T, Deng J, et al. CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis. Int J Biol Sci. 2020;16:719–29.

    Article  CAS  Google Scholar 

  35. Paul I, Ghosh MK. The E3 ligase CHIP: Insights into its structure and regulation. Biomed Res Int. 2014;2014:918183.

    Article  Google Scholar 

  36. Wu H, Luo YX, Hu W, Zhao ML, Bie J, Yang M, et al. MicroRNA-382-5p inhibits osteosarcoma development and progression by negatively regulating VEZF1 expression. Oncol Lett. 2021;22:752.

    Article  CAS  Google Scholar 

  37. Ahmed M, Lai TH, Zada S, Hwang JS, Pham TM, Yun M, et al. Functional linkage of RKIP to the epithelial to mesenchymal transition and autophagy during the development of prostate cancer. Cancers. 2018;10:273.

  38. Wudu M, Ren H, Hui L, Jiang J, Zhang S, Xu Y, et al. DRAM2 acts as an oncogene in non-small cell lung cancer and suppresses the expression of p53. J Exp Clin Cancer Res. 2019;38:72.

    Article  Google Scholar 

  39. Lim C, Xu JC, Chen TY, Xu JX, Chen WF, Hu JW, et al. Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner. Cancer Cell Int. 2020;20:45.

    Article  Google Scholar 

  40. Kuerbanjiang A, Maimaituerxun M, Zhang Y, Li Y, Cui G, Abuduhabaier A, et al. V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as a prognostic biomarker of poor outcomes in esophageal cancer patients. BMC Gastroenterol. 2021;21:86.

    Article  CAS  Google Scholar 

  41. Curtis M, Kenny HA, Ashcroft B, Mukherjee A, Johnson A, Zhang Y, et al. Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metab. 2019;29:141–155.e9.

    Article  CAS  Google Scholar 

  42. Ha SE, Kim SM, Vetrivel P, Kim HH, Bhosale PB, Heo JD, et al. Inhibition of cell proliferation and metastasis by scutellarein regulating PI3K/Akt/NF-κB signaling through PTEN activation in hepatocellular carcinoma. Int J Mol Sci. 2021;22:8841.

  43. Pietras P, Leśniczak-Staszak M, Kasprzak A, Andrzejewska M, Jopek K, Sowiński M, et al. MVP expression facilitates tumor cell proliferation and migration supporting the metastasis of colorectal cancer cells. Int J Mol Sci 2021;22:12121.

  44. Schlag K, Steinhilber D, Karas M, Sorg BL. Analysis of proximal ALOX5 promoter binding proteins by quantitative proteomics. FEBS J. 2020;287:4481–99.

    Article  CAS  Google Scholar 

  45. Mansour MA. Ubiquitination: Friend and foe in cancer. Int J Biochem Cell Biol. 2018;101:80–93.

    Article  CAS  Google Scholar 

  46. Liang Q, Tang C, Tang M, Zhang Q, Gao Y, Ge Z. TRIM47 is upregulated in colorectal cancer, promoting ubiquitination and degradation of SMAD4. J Exp Clin Cancer Res. 2019;38:159.

    Article  Google Scholar 

  47. Wu C, Luo K, Zhao F, Yin P, Song Y, Deng M, et al. USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization. Cell Death Differ. 2018;25:1855–69.

    Article  CAS  Google Scholar 

  48. Fujita Y, Tinoco R, Li Y, Senft D, Ronai ZA. Ubiquitin ligases in cancer immunotherapy—Balancing antitumor and autoimmunity. Trends Mol Med. 2019;25:428–43.

    Article  CAS  Google Scholar 

  49. Zhang S, Hu ZW, Mao CY, Shi CH, Xu YM. CHIP as a therapeutic target for neurological diseases. Cell Death Dis. 2020;11:727.

    Article  CAS  Google Scholar 

  50. Ferreira JV, Fôfo H, Bejarano E, Bento CF, Ramalho JS, Girão H, et al. STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy. Autophagy. 2013;9:1349–66.

    Article  CAS  Google Scholar 

  51. Yonezawa T, Takahashi H, Shikata S, Liu X, Tamura M, Asada S, et al. The ubiquitin ligase STUB1 regulates stability and activity of RUNX1 and RUNX1-RUNX1T1. J Biol Chem. 2017;292:12528–41.

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by Beijing Medical Award Foundation (No. HRIRF-2018-C020).

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Authors and Affiliations

  1. Department of Radiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China

    Xiaobao Shi

  2. Department of Interventional Medicine, Shengjing Hospital of China Medical University, Shenyang, China

    Pengfei Zhao & Gang Zhao

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Contributions

GZ designed the study. XS and PZ were involved in experiments and data collection. XS and GZ performed the statistical analysis and preparation of figures. XS drafted the paper. GZ revised the paper. All authors read and approved the final manuscript.

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Correspondence to Gang Zhao.

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This study was approved by the Ethics Committee of Fourth Affiliated Hospital of China Medical University in accordance with principles of the Helsinki Declaration. Informed consent of all subjects was received. Animal experiments were approved by the Experimental Animal Ethics Committee of Fourth Affiliated Hospital of China Medical University. All efforts were made to relief the suffering of animals.

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Shi, X., Zhao, P. & Zhao, G. VEZF1, destabilized by STUB1, affects cellular growth and metastasis of hepatocellular carcinoma by transcriptionally regulating PAQR4. Cancer Gene Ther 30, 256–266 (2023). https://doi.org/10.1038/s41417-022-00540-8

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