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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Metastasis | Research article

WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells

Authors: Simona Punzi, Chiara Balestrieri, Carolina D’Alesio, Daniela Bossi, Gaetano Ivan Dellino, Elena Gatti, Giancarlo Pruneri, Carmen Criscitiello, Giulia Lovati, Marine Meliksetyan, Alessandro Carugo, Giuseppe Curigliano, Gioacchino Natoli, Pier Giuseppe Pelicci, Luisa Lanfrancone

Published in: Breast Cancer Research | Issue 1/2019

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Abstract

Background

Development of metastases and drug resistance are still a challenge for a successful systemic treatment in breast cancer (BC) patients. One of the mechanisms that confer metastatic properties to the cell relies in the epithelial-to-mesenchymal transition (EMT). Moreover, both EMT and metastasis are partly modulated through epigenetic mechanisms, by repression or induction of specific related genes.

Methods

We applied shRNAs and drug targeting approaches in BC cell lines and metastatic patient-derived xenograft (PDX) models to inhibit WDR5, the core subunit of histone H3 K4 methyltransferase complexes, and evaluate its role in metastasis regulation.

Result

We report that WDR5 is crucial in regulating tumorigenesis and metastasis spreading during BC progression. In particular, WDR5 loss reduces the metastatic properties of the cells by reverting the mesenchymal phenotype of triple negative- and luminal B-derived cells, thus inducing an epithelial trait. We also suggest that this regulation is mediated by TGFβ1, implying a prominent role of WDR5 in driving EMT through TGFβ1 activation. Moreover, such EMT reversion can be induced by drug targeting of WDR5 as well, leading to BC cell sensitization to chemotherapy and enhancement of paclitaxel-dependent effects.

Conclusions

We suggest that WDR5 inhibition could be a promising pharmacologic approach to reduce cell migration, revert EMT, and block metastasis formation in BC, thus overcoming resistance to standard treatments.
Appendix
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Literature
1.
Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR, et al. The global burden of women's cancers: a grand challenge in global health. Lancet. 2017;389(10071):847–60.PubMedCrossRef
2.
3.
Meidhof S, Brabletz S, Lehmann W, Preca BT, Mock K, Ruh M, et al. ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med. 2015;7(6):831–47.PubMedPubMedCentralCrossRef
4.
Chaffer CL, San Juan BP, Lim E, Weinberg RA. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016;35(4):645–54.PubMedCrossRef
5.
Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7(2):131–42.PubMedCrossRef
6.
Jordan NV, Johnson GL, Abell AN. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle. 2011;10(17):2865–73.PubMedPubMedCentralCrossRef
7.
Micalizzi DS, Ford HL. Epithelial-mesenchymal transition in development and cancer. Future Oncol. 2009;5(8):1129–43.PubMedCrossRef
8.
Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70(3):968–78.PubMedPubMedCentralCrossRef
9.
Chen H, Lorton B, Gupta V, Shechter D. A TGFbeta-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression. Oncogene. 2017;36(3):373–86.PubMedCrossRef
10.
Lee JY, Kong G. Roles and epigenetic regulation of epithelial-mesenchymal transition and its transcription factors in cancer initiation and progression. Cell Mol Life Sci. 2016;73(24):4643–60.PubMedCrossRef
11.
Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G. Epithelial-to-Mesenchymal transition: epigenetic reprogramming driving cellular plasticity. Trends Genetics. 2017;33(12):943–59.CrossRef
12.
Ford DJ, Dingwall AK. The cancer COMPASS: navigating the functions of MLL complexes in cancer. Cancer Genet. 2015;208(5):178–91.PubMedCrossRef
13.
Chen X, Xie W, Gu P, Cai Q, Wang B, Xie Y, et al. Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation. Sci Rep. 2015;5:8293.PubMedPubMedCentralCrossRef
14.
Mungamuri SK, Murk W, Grumolato L, Bernstein E, Aaronson SA. Chromatin modifications sequentially enhance ErbB2 expression in ErbB2-positive breast cancers. Cell Rep. 2013;5(2):302–13.PubMedPubMedCentralCrossRef
15.
Carugo A, Genovese G, Seth S, Nezi L, Rose JL, Bossi D, et al. In vivo functional platform targeting patient-derived Xenografts identifies WDR5-Myc association as a critical determinant of pancreatic Cancer. Cell Rep. 2016;16(1):133–47.PubMedCrossRef
16.
Sun W, Guo F, Liu M. Up-regulated WDR5 promotes gastric cancer formation by induced cyclin D1 expression. J Cell Biochem. 2018;119(4):3304–16.PubMedCrossRef
17.
Sun Y, Bell JL, Carter D, Gherardi S, Poulos RC, Milazzo G, et al. WDR5 supports an N-Myc transcriptional complex that drives a Protumorigenic gene expression signature in neuroblastoma. Cancer Res. 2015;75(23):5143–54.PubMedCrossRef
18.
Cheng Y, Jutooru I, Chadalapaka G, Corton JC, Safe S. The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. Oncotarget. 2015;6(13):10840–52.PubMedPubMedCentralCrossRef
19.
Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell. 2011;145(2):183–97.PubMedPubMedCentralCrossRef
20.
Wang F, Han J, Wang L, Jing Y, Zhu Z, Hui D, et al. CCCTC-binding factor transcriptionally targets Wdr5 to mediate somatic cell reprogramming. Stem Cells Dev. 2017;26(10):743–50.PubMedCrossRef
21.
Lin C, Wang Y, Wang Y, Zhang S, Yu L, Guo C, et al. Transcriptional and posttranscriptional regulation of HOXA13 by lncRNA HOTTIP facilitates tumorigenesis and metastasis in esophageal squamous carcinoma cells. Oncogene. 2017;36(38):5392–406.PubMedCrossRef
22.
Malek R, Gajula RP, Williams RD, Nghiem B, Simons BW, Nugent K, et al. TWIST1-WDR5-Hottip regulates Hoxa9 chromatin to facilitate prostate Cancer metastasis. Cancer Res. 2017;77(12):3181–93.PubMedPubMedCentralCrossRef
23.
Tan X, Chen S, Wu J, Lin J, Pan C, Ying X, et al. PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407. Cell Death Dis. 2017;8(3):e2686.PubMedPubMedCentralCrossRef
24.
25.
Ge Z, Song EJ, Kawasawa YI, Li J, Dovat S, Song C. WDR5 high expression and its effect on tumorigenesis in leukemia. Oncotarget. 2016;7(25):37740–54.PubMedPubMedCentralCrossRef
26.
Wu Y, Diao P, Li Z, Zhang W, Wang D, Wang Y, et al. Overexpression of WD repeat domain 5 associates with aggressive clinicopathological features and unfavorable prognosis in head neck squamous cell carcinoma. J Oral Pathol Med. 2018;47(5):502-10.CrossRef
27.
Cui Z, Li H, Liang F, Mu C, Mu Y, Zhang X, et al. Effect of high WDR5 expression on the hepatocellular carcinoma prognosis. Oncol Lett. 2018;15(5):7864–70.PubMedPubMedCentral
28.
Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. 2011;43(5):811–22.PubMedCrossRef
29.
Punzi S, Meliksetian M, Riva L, Marocchi F, Pruneri G, Criscitiello C, et al. Development of personalized therapeutic strategies by targeting actionable vulnerabilities in metastatic and chemotherapy-resistant breast cancer PDXs. Cells. 2019;8(6):605.PubMedCentralCrossRef
30.
D'Alesio C, Punzi S, Cicalese A, Fornasari L, Furia L, Riva L, et al. RNAi screens identify CHD4 as an essential gene in breast cancer growth. Oncotarget. 2016;7(49):80901–15.PubMedPubMedCentral
31.
van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009.PubMedCrossRef
32.
Bossi D, Cicalese A, Dellino GI, Luzi L, Riva L, D'Alesio C, et al. In vivo genetic screens of patient-derived tumors revealed unexpected frailty of the transformed phenotype. Cancer Discovery. 2016;6(6):650–63.PubMedCrossRef
33.
Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836–46.PubMedPubMedCentralCrossRef
34.
Jaaks P, Bernasconi M. The proprotein convertase furin in tumour progression. Int J Cancer. 2017;141(4):654–63.PubMedCrossRef
35.
Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, et al. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest. 2003;112(7):1116–24.PubMedPubMedCentralCrossRef
36.
Jakobsson ME, Moen A, Davidson B, Falnes PO. Hsp70 (HSPA1) lysine methylation status as a potential prognostic factor in metastatic high-grade serous carcinoma. PLoS One. 2015;10(10):e0140168.PubMedPubMedCentralCrossRef
37.
Li J, Han S, Qian Z, Su X, Fan S, Fu J, et al. Genetic amplification of PPME1 in gastric and lung cancer and its potential as a novel therapeutic target. Cancer Biol Therapy. 2014;15(1):128–34.CrossRef
38.
Rodrigues-Ferreira S, Nehlig A, Monchecourt C, Nasr S, Fuhrmann L, Lacroix-Triki M, et al. Combinatorial expression of microtubule-associated EB1 and ATIP3 biomarkers improves breast cancer prognosis. Breast Cancer Res Treat. 2019;173(3):573–83.PubMedCrossRef
39.
Tanaka M, Ichikawa-Tomikawa N, Shishito N, Nishiura K, Miura T, Hozumi A, et al. Co-expression of S100A14 and S100A16 correlates with a poor prognosis in human breast cancer and promotes cancer cell invasion. BMC Cancer. 2015;15:53.PubMedPubMedCentralCrossRef
40.
Zhang H, Meng F, Wu S, Kreike B, Sethi S, Chen W, et al. Engagement of I-branching {beta}-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-{beta} signaling. Cancer Res. 2011;71(14):4846–56.PubMedPubMedCentralCrossRef
41.
Han Q, Zhou C, Liu F, Xu G, Zheng R, Zhang X. MicroRNA-196a post-transcriptionally upregulates the UBE2C proto-oncogene and promotes cell proliferation in breast cancer. Oncol Rep. 2015;34(2):877–83.PubMedCrossRef
42.
Wang P, Dreger M, Madrazo E, Williams CJ, Samaniego R, Hodson NW, et al. WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment. Proc Natl Acad Sci U S A. 2018;115(34):8581–6.PubMedPubMedCentralCrossRef
43.
Ingthorsson S, Andersen K, Hilmarsdottir B, Maelandsmo GM, Magnusson MK, Gudjonsson T. HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR. Oncogene. 2016;35(32):4244–55.PubMedCrossRef
44.
Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha N-terminal leukemia. Nat Chem Biol. 2015;11(8):571–8.PubMedPubMedCentralCrossRef
45.
Gupta A, Xu J, Lee S, Tsai ST, Zhou B, Kurosawa K, et al. Facile target validation in an animal model with intracellularly expressed monobodies. Nat Chem Biol. 2018;14(9):895–900.PubMedPubMedCentralCrossRef
46.
Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, et al. First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res. 2015;21(3):553–60.PubMedCrossRef
47.
Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Design Development Therapy. 2015;9:4479–99.PubMedPubMedCentral
48.
Olmeda D, Moreno-Bueno G, Flores JM, Fabra A, Portillo F, Cano A. SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. Cancer Res. 2007;67(24):11721–31.PubMedCrossRef
49.
50.
Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, et al. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res. 2009;15(8):2657–65.PubMedCrossRef
51.
Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004;18(10):1131–43.PubMedPubMedCentralCrossRef
52.
Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11(12):1487–95.PubMedCrossRef
53.
Wu Q, Xiang S, Ma J, Hui P, Wang T, Meng W, et al. Long non-coding RNA CASC15 regulates gastric cancer cell proliferation, migration and epithelial mesenchymal transition by targeting CDKN1A and ZEB1. Mol Oncol. 2018;12(6):799–813.PubMedPubMedCentralCrossRef
54.
55.
Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–73.PubMedCrossRef
Metadata
Title
WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells
Authors
Simona Punzi
Chiara Balestrieri
Carolina D’Alesio
Daniela Bossi
Gaetano Ivan Dellino
Elena Gatti
Giancarlo Pruneri
Carmen Criscitiello
Giulia Lovati
Marine Meliksetyan
Alessandro Carugo
Giuseppe Curigliano
Gioacchino Natoli
Pier Giuseppe Pelicci
Luisa Lanfrancone
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1216-y

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