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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage

Authors: Beth K. Neilsen, Binita Chakraborty, Jamie L. McCall, Danielle E. Frodyma, Richard L. Sleightholm, Kurt W. Fisher, Robert E. Lewis

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

KMT2/MLL proteins are commonly overexpressed or mutated in cancer and have been shown to support cancer maintenance. These proteins are responsible for methylating histone 3 at lysine 4 and promoting transcription and DNA synthesis; however, they are inactive outside of a multi-protein complex that requires WDR5. WDR5 has been implicated in cancer for its role in the COMPASS complex and its interaction with Myc; however, the role of WDR5 in colon cancer has not yet been elucidated.

Methods

WDR5 expression was evaluated using RT-qPCR and western blot analysis. Cell viability and colony forming assays were utilized to evaluate the effects of WDR5 depletion or inhibition in colon cancer cells. Downstream effects of WDR5 depletion and inhibition were observed by western blot.

Results

WDR5 is overexpressed in colon tumors and colon cancer cell lines at the mRNA and protein level. WDR5 depletion reduces cell viability in HCT116, LoVo, RKO, HCT15, SW480, SW620, and T84 colon cancer cells. Inhibition of the WDR5:KMT2/MLL interaction using OICR-9429 reduces cell viability in the same panel of cell lines albeit not to the same extent as RNAi-mediated WDR5 depletion. WDR5 depletion reduced H3K4Me3 and increased phosphorylation of H2AX in HCT116, SW620, and RKO colon cancer cells; however, OICR-9429 treatment did not recapitulate these effects in all cell lines potentially explaining the reduced toxicity of OICR-9429 treatment as compared to WDR5 depletion. WDR5 depletion also sensitized colon cancer cells to radiation-induced DNA damage.

Conclusions

These data demonstrate a clear role for WDR5 in colon cancer and future studies should examine its potential to serve as a therapeutic target in cancer. Additional studies are needed to fully elucidate if the requirement for WDR5 is independent of or consistent with its role within the COMPASS complex. OICR-9429 treatment was particularly toxic to SW620 and T84 colon cancer cells, two cell lines without mutations in WDR5 and KMT2/MLL proteins suggesting COMPASS complex inhibition may be particularly effective in tumors lacking KMT2 mutations. Additionally, the ability of WDR5 depletion to amplify the toxic effects of radiation presents the possibility of targeting WDR5 to sensitize cells to DNA-damaging therapies.
Appendix
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Literature
1.
Li BE, Ernst P. Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia. Exp Hematol. 2014;42(12):995–1012.CrossRefPubMedCentralPubMed
2.
Yang W, Ernst P. Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis. Curr Opin Hematol. 2017;24(4):322–8.CrossRefPubMedPubMedCentral
3.
Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem. 2012;81:65–95.CrossRefPubMedCentralPubMed
4.
Ford DJ, Dingwall AK. The cancer COMPASS: navigating the functions of MLL complexes in cancer. Cancer genetics. 2015;208(5):178–91.CrossRefPubMed
5.
Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K, Wong ED, Devarajan K, Daugherty AC, Kundaje AB, Mancini E, et al. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell. 2014;158(3):673–88.CrossRefPubMedCentralPubMed
6.
Chen K, Chen Z, Wu D, Zhang L, Lin X, Su J, Rodriguez B, Xi Y, Xia Z, Chen X, et al. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes. Nat Genet. 2015;47(10):1149–57.CrossRefPubMedCentralPubMed
7.
Ali A, Veeranki SN, Chinchole A, Tyagi S. MLL/WDR5 complex regulates Kif2A localization to ensure chromosome Congression and proper spindle assembly during mitosis. Dev Cell. 2017;41(6):605–22. e607CrossRefPubMed
8.
Kantidakis T, Saponaro M, Mitter R, Horswell S, Kranz A, Boeing S, Aygun O, Kelly GP, Matthews N, Stewart A, et al. Mutation of cancer driver MLL2 results in transcription stress and genome instability. Genes Dev. 2016;30(4):408–20.CrossRefPubMedCentralPubMed
9.
Esposito MT, Zhao L, Fung TK, Rane JK, Wilson A, Martin N, Gil J, Leung AY, Ashworth A, So CW. Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med. 2015;21(12):1481–90.CrossRefPubMed
10.
Dawkins JB, Wang J, Maniati E, Heward JA, Koniali L, Kocher HM, Martin SA, Chelala C, Balkwill FR, Fitzgibbon J, et al. Reduced expression of histone Methyltransferases KMT2C and KMT2D correlates with improved outcome in pancreatic ductal adenocarcinoma. Cancer Res. 2016;76(16):4861–71.CrossRefPubMedCentralPubMed
11.
Guo C, Chen LH, Huang Y, Chang CC, Wang P, Pirozzi CJ, Qin X, Bao X, Greer PK, McLendon RE, et al. KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget. 2013;4(11):2144–53.CrossRefPubMedCentralPubMed
12.
Zhang C, Song C, Liu T, Tang R, Chen M, Gao F, Xiao B, Qin G, Shi F, Li W, et al. KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway. Cell Death Dis. 2017;8(7):e2940.CrossRefPubMedCentralPubMed
13.
Mo R, Rao SM, Zhu YJ. Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. J Biol Chem. 2006;281(23):15714–20.CrossRefPubMed
14.
Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M, Dickler MN, Scaltriti M, Leslie CS, Armstrong SA, et al. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science. 2017;355(6331):1324–30.CrossRefPubMedCentralPubMed
15.
Kim JY, Banerjee T, Vinckevicius A, Luo Q, Parker JB, Baker MR, Radhakrishnan I, Wei JJ, Barish GD, Chakravarti D. A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer. Mol Cell. 2014;54(4):613–25.CrossRefPubMedCentralPubMed
16.
Malik R, Khan AP, Asangani IA, Cieslik M, Prensner JR, Wang X, Iyer MK, Jiang X, Borkin D, Escara-Wilke J, et al. Targeting the MLL complex in castration-resistant prostate cancer. Nat Med. 2015;21(4):344–52.CrossRefPubMedCentralPubMed
17.
Mouradov D, Sloggett C, Jorissen RN, Love CG, Li S, Burgess AW, Arango D, Strausberg RL, Buchanan D, Wormald S, et al. Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. Cancer Res. 2014;74(12):3238–47.CrossRefPubMed
18.
Roig AI, Eskiocak U, Hight SK, Kim SB, Delgado O, Souza RF, Spechler SJ, Wright WE, Shay JW. Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro. Gastroenterology. 2010;138(3):1012–21. e1011–1015CrossRefPubMed
19.
Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, Skucha A, Vittori S, Kuznetsova E, Smil D, et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha N-terminal leukemia. Nat Chem Biol. 2015;11(8):571–8.CrossRefPubMedCentralPubMed
20.
Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature. 2013;493(7434):689–93.CrossRefPubMedCentralPubMed
21.
Getlik M, Smil D, Zepeda-Velazquez C, Bolshan Y, Poda G, Wu H, Dong A, Kuznetsova E, Marcellus R, Senisterra G, et al. Structure-based optimization of a small molecule antagonist of the interaction between WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia 1 (MLL1). J Med Chem. 2016;59(6):2478–96.CrossRefPubMed
22.
Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A. Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes Dev. 2014;28(9):929–42.CrossRefPubMedCentralPubMed
23.
Ruthenburg AJ, Wang W, Graybosch DM, Li H, Allis CD, Patel DJ, Verdine GL. Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex. Nat Struct Mol Biol. 2006;13(8):704–12.CrossRefPubMedCentralPubMed
24.
Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol. 2006;13(8):713–9.CrossRefPubMed
25.
Couture JF, Collazo E, Trievel RC. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 2006;13(8):698–703.CrossRefPubMed
26.
Han Z, Guo L, Wang H, Shen Y, Deng XW, Chai J. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol Cell. 2006;22(1):137–44.CrossRefPubMed
27.
Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT, Badenhorst P, et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature. 2006;442(7098):86–90.CrossRefPubMed
28.
Wysocka J, Swigut T, Milne TA, Dou Y, Zhang X, Burlingame AL, Roeder RG, Brivanlou AH, Allis CD. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell. 2005;121(6):859–72.CrossRefPubMed
29.
Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472(7341):120–4.CrossRefPubMedCentralPubMed
30.
Xu Z, Gao X, He Y, Ju J, Zhang M, Liu R, Wu Y, Ma C, Ma C, Lin Z, et al. Synergistic effect of SRY and its direct target, WDR5, on Sox9 expression. PLoS One. 2012;7(4):e34327.CrossRefPubMedCentralPubMed
31.
Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, Ding J, Ge Y, Darr H, Chang B, et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell. 2011;145(2):183–97.CrossRefPubMedCentralPubMed
32.
Yang YW, Flynn RA, Chen Y, Qu K, Wan B, Wang KC, Lei M, Chang HY. Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency. eLife. 2014;3:e02046.PubMedCentralCrossRefPubMed
33.
34.
Migliori V, Muller J, Phalke S, Low D, Bezzi M, Mok WC, Sahu SK, Gunaratne J, Capasso P, Bassi C, et al. Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. Nat Struct Mol Biol. 2012;19(2):136–44.CrossRefPubMed
35.
36.
Quagliata L, Matter MS, Piscuoglio S, Arabi L, Ruiz C, Procino A, Kovac M, Moretti F, Makowska Z, Boldanova T, et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 2014;59(3):911–23.CrossRefPubMed
37.
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.CrossRefPubMedCentralPubMed
38.
Chen X, Xie W, Gu P, Cai Q, Wang B, Xie Y, Dong W, He W, Zhong G, Lin T, et al. Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation. Sci Rep. 2015;5:8293.CrossRefPubMedCentralPubMed
39.
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.CrossRefPubMedCentralPubMed
40.
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.CrossRefPubMedCentralPubMed
41.
Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, Teng SC, Wu KJ. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. 2011;43(5):811–22.CrossRefPubMed
42.
Tan X, Chen S, Wu J, Lin J, Pan C, Ying X, Pan Z, Qiu L, Liu R, Geng R, et al. PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407. Cell Death Dis. 2017;8(3):e2686.CrossRefPubMedCentralPubMed
43.
Malek R, Gajula RP, Williams RD, Nghiem B, Simons BW, Nugent K, Wang H, Taparra K, Lemtiri-Chlieh G, Yoon AR, et al. TWIST1-WDR5-Hottip regulates Hoxa9 chromatin to facilitate prostate Cancer metastasis. Cancer Res. 2017;77(12):3181–93.CrossRefPubMedCentralPubMed
44.
Fu Z, Chen C, Zhou Q, Wang Y, Zhao Y, Zhao X, Li W, Zheng S, Ye H, Wang L, et al. LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9. Cancer Lett. 2017;410:68–81.CrossRefPubMed
45.
Lin C, Wang Y, Wang Y, Zhang S, Yu L, Guo C, Xu H. Transcriptional and posttranscriptional regulation of HOXA13 by lncRNA HOTTIP facilitates tumorigenesis and metastasis in esophageal squamous carcinoma cells. Oncogene. 2017;36(38):5392–406.CrossRefPubMed
46.
Chang S, Liu J, Guo S, He S, Qiu G, Lu J, Wang J, Fan L, Zhao W, Che X. HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression. Oncol Rep. 2016;35(6):3577–85.CrossRefPubMed
47.
48.
Sun W, Guo F, Liu M. Up-regulated WDR5 promotes gastric cancer formation by induced cyclin D1 expression. J Cell Biochem. 2017;119(4)3304–3316.
49.
Sun TT, He J, Liang Q, Ren LL, Yan TT, Yu TC, Tang JY, Bao YJ, Hu Y, Lin Y, et al. LncRNA GClnc1 promotes gastric carcinogenesis and may act as a modular scaffold of WDR5 and KAT2A complexes to specify the histone modification pattern. Cancer discovery. 2016;6(7):784–801.CrossRefPubMed
50.
Sun Y, Bell JL, Carter D, Gherardi S, Poulos RC, Milazzo G, Wong JW, Al-Awar R, Tee AE, Liu PY, 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.CrossRefPubMed
51.
Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, Olejniczak ET, Clark T, Dey S, Lorey S, et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell. 2015;58(3):440–52.CrossRefPubMedCentralPubMed
52.
53.
Ullius A, Luscher-Firzlaff J, Costa IG, Walsemann G, Forst AH, Gusmao EG, Kapelle K, Kleine H, Kremmer E, Vervoorts J, et al. The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification. Nucleic Acids Res. 2014;42(11):6901–20.CrossRefPubMedCentralPubMed
54.
Lorenzin F, Benary U, Baluapuri A, Walz S, Jung LA, von Eyss B, Kisker C, Wolf J, Eilers M, Wolf E. Different promoter affinities account for specificity in MYC-dependent gene regulation. eLife. 2016;5:e15161.
55.
Carugo A, Genovese G, Seth S, Nezi L, Rose JL, Bossi D, Cicalese A, Shah PK, Viale A, Pettazzoni PF, 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.CrossRefPubMed
56.
Blumenthal DT, Dvir A, Lossos A, Tzuk-Shina T, Lior T, Limon D, Yust-Katz S, Lokiec A, Ram Z, Ross JS, et al. Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J Neuro-Oncol. 2016;130(1):211–9.CrossRef
57.
Bailey JK, Fields AT, Cheng K, Lee A, Wagenaar E, Lagrois R, Schmidt B, Xia B, Ma D. WD repeat-containing protein 5 (WDR5) localizes to the midbody and regulates abscission. J Biol Chem. 2015;290(14):8987–9001.CrossRefPubMedCentralPubMed
58.
De Haro LP, Wray J, Williamson EA, Durant ST, Corwin L, Gentry AC, Osheroff N, Lee SH, Hromas R, Nickoloff JA. Metnase promotes restart and repair of stalled and collapsed replication forks. Nucleic Acids Res. 2010;38(17):5681–91.CrossRefPubMedCentralPubMed
59.
Kim K, Punj V, Choi J, Heo K, Kim JM, Laird PW, An W. Gene dysregulation by histone variant H2A.Z in bladder cancer. Epigenetics Chromatin. 2013;6(1):34.CrossRefPubMedCentralPubMed
Metadata
Title
WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage
Authors
Beth K. Neilsen
Binita Chakraborty
Jamie L. McCall
Danielle E. Frodyma
Richard L. Sleightholm
Kurt W. Fisher
Robert E. Lewis
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4580-6

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