Huwe1 inactivation promotes ovarian cancer metastasis by extracellular matrix deregulation

Objective: Huwe1 is critical for promoting the progression of a range of malignancies including ovarian cancer. Still, its role in ovarian cancer metastasis has not been reported. The goal of our study was to evaluate a correlation between Huwe1 and ovarian cancer metastasis. Methods: The mouse ovary surface epithelium (MOSE) cells isolated from Huwe1L/L${}^{L/L}$ mice were identified by flow cytometry assay. Cell migration and invasion were analyzed by transwell system. The molecular mechanism of Huwe1 in ovarian cancer migration and invasion was explored by analyzing the difference of RNAseq data between MOSE-Huwe1L/L${}^{L/L}$-CreER and MOSE-Huwe1L/L${}^{L/L}$-Cre cells. Results: Huwe1 deletion significantly promoted tumor migration and invasion in ovarian cancer cells. Moreover, tumor cells were more frequently detected in the blood when the mice bearing allografts were treated with tamoxifen. Transcriptome analysis indicated that this phenotype may be due to the alteration in cell adhesion caused by the Huwe1 knockout. Conclusion: Huwe1 inactivation promoted ovarian cancer metastasis by the extracellular matrix (ECM) deregulation.

Huwe1; Invasion; Ovarian cancer; MOSE cells; Extracellular matrix

[1] Yang D, Cheng D, Tu Q, Yang H, Sun B, Yan L, et al. Huwe1 controls the development of non-small cell lung cancer through down-regulation of p53. Theranostics. 2018; 8: 3517–3529.

[2] Su C, Wang T, Zhao J, Cheng J, Hou J. Meta-analysis of gene expression alterations and clinical significance of the HECT domain-containing ubiquitin ligase Huwe1 in cancer. Oncology Letters. 2019; 18: 2292–2303.

[3] Vaughan L, Tan C, Chapman A, Nonaka D, Mack NA, Smith D, et al. Huwe1 Ubiquitylates and Degrades the RAC Activator TIAM1 Promoting Cell-Cell Adhesion Disassembly, Migration, and Invasion. Cell Reports. 2015; 10: 88–102.

[4] Ma W, Zhao P, Zang L, Zhang K, Liao H, Hu Z. Tumour suppressive function of Huwe1 in thyroid cancer. Journal of Biosciences. 2016; 41: 395–405.

[5]

Yeung T, Leung CS, Yip K, Au Yeung CL, Wong STC, Mok SC. Cellular and molecular processes in ovarian cancer metas-tasis. a Review in the Theme: Cell and Molecular Processes in Cancer Metastasis. American Journal of Physiology-Cell Physiology. 2015; 309: C444–C456.

[6]

Lowry KP, Lee SI. Imaging and Screening of Ovarian Cancer. Radiologic Clinics of North America. 2017; 55: 1251–1259.

[7] Su C, Wang T, Zhao JB, Cheng J, Hou JJ. Meta-analysis of gene expression alterations and clinical significance of the HECT domain-containing ubiquitin ligase Huwe1 in cancer. Oncology Letters. 2019; 18: 2292–2303.

[8] Podgorska A, Rembiszewska A, Szafron L, Konopka B, Lukasik M, Budzilowska A, et al. Clinical significance of Huwe1 expression in ovarian cancer. European Journal of Cancer. 2015; 51: S94.

[9] Yang D, Sun B, Zhang X, Cheng D, Yu X, Yan L, et al. Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade. Cancer Research. 2017; 77: 4773–4784.

[10] Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G, Nikitin AY. Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature. 2013; 495: 241–245.

[11] Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 2012; 338: 1080–1084.

[12] Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nature Protocols. 2012; 7: 562–578.

[13] Confalonieri S, Quarto M, Goisis G, Nuciforo P, Donzelli M, Jodice G, et al. Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor. Oncogene. 2009; 28: 2959–2968.

[14] Wang X, Lu G, Li L, Yi J, Yan K, Wang Y, et al. Huwe1 interacts with BRCA1 and promotes its degradation in the ubiquitin-proteasome pathway. Biochemical and Biophysical Research Communications. 2014; 444: 549–554.

[15] He Y, Zhou J, Wan Q. The E3 ligase Huwe1 mediates TGFBR2 ubiquitination and promotes gastric cancer cell proliferation, migration, and invasion. Investigational New Drugs. 2021; 39: 713–723.

[16] Inoue S, Hao Z, Elia AJ, Cescon D, Zhou L, Silvester J, et al. Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. Genes and Development. 2013; 27: 1101–1114.

[17] Peter S, Bultinck J, Myant K, Jaenicke LA, Walz S, Müller J, et al. Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the Huwe1 ubiquitin ligase. EMBO Molecular Medicine. 2014; 6: 1525–1541.

[18] Yuzhalin AE, Gordon-Weeks AN, Tognoli ML, Jones K, Markelc B, Konietzny R, et al. Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix. Nature Communications. 2018; 9: 4783.

[19] Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013; 22: S66–S72.

[20] Barash U, Cohen-Kaplan V, Dowek I, Sanderson RD, Ilan N, Vlodavsky I. Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasis. The FEBS Journal. 2010; 277: 3890–3903.

[21] Zhu Z, Song J, Guo Y, Huang Z, Chen X, Dang X, et al. LAMB3 promotes tumour progression through the AKT–FOXO34 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer. Oncogene. 2020; 39: 4666–4680.

[22] Cao T, Jiang Y, Wang Z, Zhang N, Al-Hendy A, Mamillapalli R, et al. H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas. Oncogene. 2019; 38: 5356–5366.

[23] Sim H, Hu B, Viapiano MS. Reduced expression of the hyaluronan and proteoglycan link proteins in malignant gliomas. The Journal of Biological Chemistry. 2009; 284: 26547–26556.

[24] Chen L, Liu D, Yi X, Qi L, Tian X, Sun B, et al. The novel miR-1269b-regulated protein SVEP1 induces hepatocellular carcinoma proliferation and metastasis likely through the PI3K/Akt pathway. Cell Death and Disease. 2020; 11: 320.

[25] Wang W, Gao W, Zhang L, Zhang D, Zhao Z, Bao Y. Deoxy-podophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells. Oncology Reports. 2019; 41: 2453–2463.

[26] Bhatnagar R, Dabholkar J, Saranath D. Genome-wide disease association study in chewing tobacco associated oral cancers. Oral Oncology. 2012; 48: 831–835.

[27] Yao X, Zhang H, Liu Y, Liu X, Wang X, Sun X, et al. MiR-99b-3p promotes hepatocellular carcinoma metastasis and proliferation by targeting protocadherin 19. Gene. 2019; 698: 141–149.

[28] Gao F, Huang W, Zhang Y, Tang S, Zheng L, Ma F, et al. Hes1 promotes cell proliferation and migration by activating Bmi-1 and PTEN/Akt/GSK3β pathway in human colon cancer. Oncotarget. 2015; 6: 38667–38680.

[29] Li Y, Zhang Y, Liu X, Wang M, Wang P, Yang J, et al. Lutein inhibits proliferation, invasion and migration of hypoxic breast cancer cells via downregulation of HES1. International Journal of Oncology. 2018; 52: 2119–2129.

[30] Yi Y, Tsai SH, Cheng JC, Wang EY, Anglesio MS, Cochrane DR, et al. APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner. Gynecologic Oncology. 2017; 147: 663–671.

[31] Huang Z, Lin B, Pan H, Du J, He R, Zhang S, et al. Gene expression profile analysis of ENO1 knockdown in gastric cancer cell line MGC-803. Oncology Letters. 2019; 17: 3881–3889.