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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Pancreatic Cancer | Research

The LIM protein Ajuba/SP1 complex forms a feed forward loop to induce SP1 target genes and promote pancreatic cancer cell proliferation

Authors: Bosen Zhang, Liwei Song, Jiali Cai, Lei Li, Hong Xu, Mengying Li, Jiamin Wang, Minmin Shi, Hao Chen, Hao Jia, Zhaoyuan Hou

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

The aim of this study is to explore the molecular mechanism of the LIM protein Ajuba and the transcription factor SP1 in the pathogenesis and progression of PDAC. Ajuba is a newly defined transcriptional co-regulator and plays important role in various cancer development, while SP1 is a classic transcription factor, and is closely related with a variety of gene expression and cancer development including PDAC.

Methods

The expression of Ajuba and SP1 in PDAC tissues was detected by immunohistochemistry (IHC), and the correlation between expression level and clinical prognosis of Ajuba and SP1 was extensively analyzed using online tools. The interaction between Ajuba and SP1 was examined by co-immunoprecipitation (co-IP) and GST-pulldown assays. Stable cell lines were established via lentiviral infection, and was examined by qRT-PCR and western blot assays. The effects of Ajuba/SP1 on PDAC cell proliferation were examined using CCK8 and colony formation assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were employed to examine the transcription activity.

Results

The expression level (protein and mRNA) of Ajuba and SP1 was elevated in PDAC tissues and was positively correlated; patients with high Ajuba and SP1 expression had a poor prognosis. Mechanistically, Ajuba binds to the C-terminus of SP1 and functions as a co-activator to enhance SP1 gene expression and promote cell proliferation; the promoter of Ajuba contains functional SP1 responsive elements and Ajuba itself is a target gene of SP1.

Conclusion

Ajuba functions as a co-activator of SP1 to induce its target gene, and that Ajuba itself is a target genes of SP1. Ajuba/SP1 complex could form a feed forward loop to drive SP1 target gene transcription and promote cell proliferation of pancreatic cancer cells. Ajuba and SP1 might be biomarkers for PDAC diagnostics, prognosis and targets for new therapeutics.
Literature
1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.CrossRef
2.
Yokoyama Y, Nimura Y, Nagino M. Advances in the treatment of pancreatic cancer: limitations of surgery and evaluation of new therapeutic strategies. Surg Today. 2009;39(6):466e75.CrossRef
3.
Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049–57.CrossRef
4.
Marie H, Pratt SJ, Betson M, Epple H, Kittler JT, Meek L, Moss SJ, Troyanovsky S, Attwell D, Longmore GD, et al. The LIM protein Ajuba is recruited to cadherin-dependent cell junctions through an association with alpha-catenin. J Biol Chem. 2003;278:1220–8.CrossRef
5.
Nola S, Daigaku R, Smolarczyk K, Carstens M, Martin-Martin B, Longmore G, Bailly M, Braga VM. Ajuba is required for Rac activation and maintenance of E-cadherin adhesion. J Cell Biol. 2011;195:855–71.CrossRef
6.
Pratt SJ, Epple H, Ward M, Feng Y, Braga VM, Longmore GD. The LIM protein Ajuba influences p130Cas localization and Rac1 activity during cell migration. J Cell Biol. 2005;168:813–24.CrossRef
7.
Jagannathan R, Schimizzi GV, Zhang K, Loza AJ, Yabuta N, Nojima H, Longmore GD. AJUBA LIM proteins limit hippo activity in proliferating cells by sequestering the hippo Core kinase complex in the cytosol. Mol Cell Biol. 2016;36(20):2526–42.CrossRef
8.
Rauskolb C, Sun S, Sun G, Pan Y, Irvine KD. Cytoskeletal tension inhibits hippo signaling through an Ajuba-warts complex. Cell. 2014;158(1):143–56.CrossRef
9.
Jia, H., Song, L., Cong, Q., Wang, J., Xu, H., Chu, Y., Li, Q., Zhang, Y., Zou, X., Zhang, C. et al. (2017) The LIM protein AJUBA promotes colorectal cancer cell survival through suppression of JAK1/STAT1/IFIT2 network. Oncogene. 2017 May 11;36(19):2655-2666.CrossRef
10.
Hou Z, Peng H, Ayyanathan K, Yan KP, Langer EM, Longmore GD, Rauscher FJ 3rd. The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression. Mol Cell Biol. 2008;28:3198–207.CrossRef
11.
Montoya-Durango DE, Velu CS, Kazanjian A, Rojas ME, Jay CM, Longmore GD, Grimes HL. Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor. J Biol Chem. 2008;283(46):32056–65.CrossRef
12.
Hou Z, Peng H, White DE, Negorev DG, Maul GG, Feng Y, Longmore GD, Waxman S, Zelent A, Rauscher FJ. LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling. Proc Natl Acad Sci. 2010;107:2938–43.CrossRef
13.
Fan H, Dong W, Li Q, Zou X, Zhang Y, Wang J, Li S, Liu W, Dong Y, Sun H, et al. Ajuba preferentially binds LXRalpha/RXRgamma heterodimer to enhance LXR target gene expression in liver cells. Mol Endocrinol. 2015;29:1608–18.CrossRef
14.
Li Q, Peng H, Fan H, Zou X, Liu Q, Zhang Y, Xu H, Chu Y, Wang C, Ayyanathan K, et al. The LIM protein Ajuba promotes adipogenesis by enhancing PPARgamma and p300/CBP interaction. Cell Death Differ. 2016;23:158–68.CrossRef
15.
Zhang M, Singh R, Peng S, Mazumdar T, Sambandam V, Shen L, Tong P, Li L, Kalu NN, Pickering CR, Frederick M, Myers JN, Wang J, Johnson FM. Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors. Cancer Lett. 2017;392:71–82.CrossRef
16.
17.
Beishline K, Azizkhan-Clifford J. Sp1 and the ‘hallmarks of cancer’. FEBS J. 2015;282(2):224–58.CrossRef
18.
Vizcaíno C, Mansilla S, Portugal J. Sp1 transcription factor: a long-standing target in cancer chemotherapy. Pharmacol Ther. 2015;152:111–24.CrossRef
19.
Jiang NY, Woda BA, Banner BF, Whalen GF, Dresser KA, Lu D. Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomark Prev. 2008;17(7):1648–52.CrossRef
20.
Kageyama R, Merlino GT, Pastan I. Epidermal growth factor (EGF) receptor gene transcription. Requirement for Sp1 and an EGF receptor-specific factor. J Biol Chem. 1988;263(13):6329–36.PubMed
21.
Hu H, Han T, Zhuo M, Wu LL, Yuan C, Wu L, Lei W, Jiao F, Wang LW. Elevated COX-2 expression promotes angiogenesis through EGFR/p38-MAPK/Sp1-dependent Signalling in pancreatic Cancer. Sci Rep. 2017;7(1):470.CrossRef
22.
Kitadai Y, Yasui W, Yokozaki H, Kuniyasu H, Haruma K, Kajiyama G, Tahara E. The level of a transcription factor Sp1 is correlated with the expression of EGF receptor in human gastric carcinomas. Biochem Biophys Res Commun. 1992;189(3):1342–8.CrossRef
23.
Maor S, Mayer D, Yarden RI, Lee AV, Sarfstein R, Werner H, Papa MZ. Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol. 2006;191(3):605–12.CrossRef
24.
Liu N, Ding D, Hao W, Yang F, Wu X, Wang M, Xu X, Ju Z, Liu JP, Song Z, Shay JW, Guo Y, Cong YS. hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor. Nucleic Acids Res. 2016;44(18):8693–703.CrossRef
25.
Chen J, Xu H, Zou X, Wang J, Zhu Y, Chen H, Shen B, Deng X, Zhou A, Chin YE, Rauscher FJ 3rd, Peng C, Hou Z. Snail recruits Ring1B to mediate transcriptional repression and cell migration in pancreatic cancer cells. Cancer Res. 2014;74(16):4353–63.CrossRef
26.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.CrossRef
27.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRef
28.
Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, Mouradov D, Sieber OM, Simpson RJ, Salim A, Bacic A, Hill AF, Stroud DA, Ryan MT, Agbinya JI, Mariadason JM, Burgess AW, Mathivanan S. FunRich: an open access standalone functional enrichment and interaction network analysis tool. Proteomics. 2015;15(15):2597–601.CrossRef
29.
30.
Li J, et al. Sp1 and KLF15 regulate basal transcription of the human LRP5 gene. BMC Genet. 2010;11:12.CrossRef
31.
Kim HJ, et al. Transcription factor Sp1 regulates basal transcription of the human DRG2 gene. Biochim Biophys Acta. 2011;1809:184–90.CrossRef
32.
Kanungo J, Pratt SJ, Marie H, Longmore GD. Ajuba, a cytosolic LIM protein, shuttles into the nucleus and affects embryonal cell proliferation and fate decisions. Mol Biol Cell. 2000;11:3299–313.CrossRef
33.
Metadata
Title
The LIM protein Ajuba/SP1 complex forms a feed forward loop to induce SP1 target genes and promote pancreatic cancer cell proliferation
Authors
Bosen Zhang
Liwei Song
Jiali Cai
Lei Li
Hong Xu
Mengying Li
Jiamin Wang
Minmin Shi
Hao Chen
Hao Jia
Zhaoyuan Hou
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1203-2

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