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LAMB3 promotes tumour progression through the AKT–FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer

Oncogene volume 39, pages 4666–4680 (2020)Cite this article

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Abstract

Aberrant expression of laminin-332 promotes tumour growth and metastasis in multiple cancers. However, the dysregulated expression and mechanism of action of LAMB3, which encodes the β3 subunit of laminin-332, and the mechanism underlying dysregulated LAMB3 expression in CRC remain obscure. Here, we show that LAMB3 is overexpressed in CRC and that this overexpression is correlated with tumour metastasis and poor prognosis. Overexpression of LAMB3 promoted cell proliferation and cell migration in vitro and tumour growth and metastasis in vivo, while knockdown of LAMB3 elicited opposing effects. LAMB3 inhibited the tumour suppressive function of FOXO3/4 by activating AKT in CRC. Both the BET inhibitor JQ1 and the MEK inhibitor U0126 decreased the mRNA level of LAMB3 in multiple CRC cells. Mechanistically, ELK4 cooperated with BRD2 to regulate the transcription of LAMB3 in CRC by directly binding to the ETS binding motifs in the LAMB3 promoter. ELK4 was as acetylated at K125, which enhanced the interaction between ELK4 and BRD2. JQ1 disrupted the interaction between ELK4 and BRD2, resulting in decreased binding of BRD2 to the LAMB3 promoter and downregulation of LAMB3 transcription. Both ELK4 and BRD2 expression was associated with LAMB3 expression in CRC. LAMB3 expression was also negatively correlated with FOXO3/4 in CRC. Our study reveals the pro-tumorigenic role of LAMB3 through the AKT–FOXO3/4 axis and the transcriptional mechanism of LAMB3 in CRC, demonstrating that LAMB3 is a potential therapeutic target that can be targeted by BET inhibitors and MEK inhibitors.

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Fig. 1: LAMB3 is overexpressed and is a marker of poor prognosis in CRC.
Fig. 2: LAMB3 promotes cell proliferation and cell migration in CRC in vitro and tumour growth and metastasis in CRC in vivo.
Fig. 3: LAMB3 promotes cell proliferation and cell migration through the AKT–FOXO3/4 axis.
Fig. 4: JQ1 inhibits the mRNA expression of LAMB3 in CRC.
Fig. 5: ELK4 interacts with BRD2 to regulate LAMB3 transcription.
Fig. 6: Acetylation-dependent interaction between ELK4 and BRD2.
Fig. 7: Clinical correlation of ELK4/BRD2–LAMB3 and LAMB3–FOXO3/4 in CRC.

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References

  1. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–32.

    Article  PubMed  Google Scholar 

  2. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244:254–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kai F, Drain AP, Weaver VM. The extracellular matrix modulates the metastatic journey. Dev Cell. 2019;49:332–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Domogatskaya A, Rodin S, Tryggvason K. Functional diversity of laminins. Annu Rev Cell Dev Biol. 2012;28:523–53.

    Article  CAS  PubMed  Google Scholar 

  5. Fukushima Y, Ohnishi T, Arita N, Hayakawa T, Sekiguchi K. Integrin alpha3beta1-mediated interaction with laminin-5 stimulates adhesion, migration and invasion of malignant glioma cells. Int J Cancer. 1998;76:63–72.

    Article  CAS  PubMed  Google Scholar 

  6. Kwon OH, Park JL, Kim M, Kim JH, Lee HC, Kim HJ, et al. Aberrant up-regulation of LAMB3 and LAMC2 by promoter demethylation in gastric cancer. Biochem Biophys Res Commun. 2011;406:539–45.

    Article  CAS  PubMed  Google Scholar 

  7. Lohi J, Oivula J, Kivilaakso E, Kiviluoto T, Frojdman K, Yamada Y, et al. Basement membrane laminin-5 is deposited in colorectal adenomas and carcinomas and serves as a ligand for alpha3beta1 integrin. APMIS. 2000;108:161–72.

    Article  CAS  PubMed  Google Scholar 

  8. Moriya Y, Niki T, Yamada T, Matsuno Y, Kondo H, Hirohashi S. Increased expression of laminin-5 and its prognostic significance in lung adenocarcinomas of small size. An immunohistochemical analysis of 102 cases. Cancer. 2001;91:1129–41.

    Article  CAS  PubMed  Google Scholar 

  9. Pyke C, Romer J, Kallunki P, Lund LR, Ralfkiaer E, Dano K, et al. The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers. Am J Pathol. 1994;145:782–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tani T, Lumme A, Linnala A, Kivilaakso E, Kiviluoto T, Burgeson RE, et al. Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane. Am J Pathol. 1997;151:1289–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Olsen J, Kirkeby LT, Brorsson MM, Dabelsteen S, Troelsen JT, Bordoy R, et al. Converging signals synergistically activate the LAMC2 promoter and lead to accumulation of the laminin gamma 2 chain in human colon carcinoma cells. Biochem J. 2003;371(Pt 1):211–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hlubek F, Jung A, Kotzor N, Kirchner T, Brabletz T. Expression of the invasion factor laminin gamma2 in colorectal carcinomas is regulated by beta-catenin. Cancer Res. 2001;61:8089–93.

    CAS  PubMed  Google Scholar 

  13. Huang Z, Zhao J, Deng W, Chen Y, Shang J, Song K, et al. Identification of a cellularly active SIRT6 allosteric activator. Nat Chem Biol. 2018;14:1118–26.

    Article  CAS  PubMed  Google Scholar 

  14. Stathis A, Bertoni F. BET proteins as targets for anticancer treatment. Cancer Discov. 2018;8:24–36.

    Article  CAS  PubMed  Google Scholar 

  15. Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, et al. Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell. 2014;25:210–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Blee AM, Liu S, Wang L, Huang H. BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion. Oncotarget. 2016;7:38319–32.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Roe JS, Mercan F, Rivera K, Pappin DJ, Vakoc CR. BET bromodomain inhibition suppresses the function of hematopoietic transcription factors in acute myeloid leukemia. Mol Cell. 2015;58:1028–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, et al. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. Proc Natl Acad Sci USA. 2011;108:E159–68.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J, et al. Brd4 maintains constitutively active NF-kappaB in cancer cells by binding to acetylated RelA. Oncogene. 2014;33:2395–404.

    Article  CAS  PubMed  Google Scholar 

  20. le Rolle AF, Chiu TK, Fara M, Shia J, Zeng Z, Weiser MR, et al. The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts. J Transl Med. 2015;13:199.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Chen X, Du P, She J, Cao L, Li Y, Xia H. Loss of ZG16 is regulated by miR-196a and contributes to stemness and progression of colorectal cancer. Oncotarget. 2016;7:86695–703.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Feng M, Feng J, Chen W, Wang W, Wu X, Zhang J, et al. Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-kappaB-dependent activation of snail and epithelial mesenchymal transition. Mol Cancer. 2016;15:77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Oh BY, Hong HK, Lee WY, Cho YB. Animal models of colorectal cancer with liver metastasis. Cancer Lett. 2017;387:114–20.

    Article  CAS  PubMed  Google Scholar 

  24. Choma DP, Milano V, Pumiglia KM, DiPersio CM. Integrin alpha3beta1-dependent activation of FAK/Src regulates Rac1-mediated keratinocyte polarization on laminin-5. J Invest Dermatol. 2007;127:31–40.

    Article  CAS  PubMed  Google Scholar 

  25. Manohar A, Shome SG, Lamar J, Stirling L, Iyer V, Pumiglia K, et al. Alpha 3 beta 1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway. J Cell Sci. 2004;117(Pt 18):4043–54.

    Article  CAS  PubMed  Google Scholar 

  26. Nguyen BP, Gil SG, Carter WG. Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling. J Biol Chem. 2000;275:31896–907.

    Article  CAS  PubMed  Google Scholar 

  27. Plas DR, Thompson CB. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem. 2003;278:12361–6.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang F, Virshup DM, Cheong JK. Oncogenic RAS-induced CK1alpha drives nuclear FOXO proteolysis. Oncogene. 2018;37:363–76.

    Article  CAS  PubMed  Google Scholar 

  29. Wu T, Wang G, Chen W, Zhu Z, Liu Y, Huang Z, et al. Co-inhibition of BET proteins and NF-kappaB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions. Cell Death Dis. 2018;9:315.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Ma Y, Wang L, Neitzel LR, Loganathan SN, Tang N, Qin L, et al. The MAPK pathway regulates intrinsic resistance to BET inhibitors in colorectal cancer. Clin Cancer Res. 2017;23:2027–37.

    Article  CAS  PubMed  Google Scholar 

  31. Sizemore GM, Pitarresi JR, Balakrishnan S, Ostrowski MC. The ETS family of oncogenic transcription factors in solid tumours. Nat Rev Cancer. 2017;17:337–51.

    Article  CAS  PubMed  Google Scholar 

  32. Baeza J, Smallegan MJ, Denu JM. Mechanisms and dynamics of protein acetylation in mitochondria. Trends Biochem Sci. 2016;41:231–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li QJ, Yang SH, Maeda Y, Sladek FM, Sharrocks AD, Martins-Green M. MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300. EMBO J. 2003;22:281–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–w102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tsuruta D, Kobayashi H, Imanishi H, Sugawara K, Ishii M, Jones JC. Laminin-332-integrin interaction: a target for cancer therapy? Curr Med Chem. 2008;15:1968–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang XM, Li J, Yan MX, Liu L, Jia DS, Geng Q, et al. Integrative analyses identify osteopontin, LAMB3 and ITGB1 as critical pro-metastatic genes for lung cancer. PLoS ONE. 2013;8:e55714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang H, Pan YZ, Cheung M, Cao M, Yu C, Chen L, et al. LAMB3 mediates apoptotic, proliferative, invasive, and metastatic behaviors in pancreatic cancer by regulating the PI3K/Akt signaling pathway. Cell Death Dis. 2019;10:230.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Jung SN, Lim HS, Liu L, Chang JW, Lim YC, Rha KS, et al. LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals. Sci Rep. 2018;8:2718.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Zhou Y, Dang J, Chang KY, Yau E, Aza-Blanc P, Moscat J, et al. miR-1298 inhibits mutant KRAS-driven tumor growth by repressing FAK and LAMB3. Cancer Res. 2016;76:5777–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Irifune H, Nishimori H, Watanabe G, Yoshida K, Ikeda T, Matsui C, et al. Aberrant laminin beta3 isoforms downstream of EWS-ETS fusion genes in Ewing family tumors. Cancer Biol Ther. 2005;4:449–55.

    Article  CAS  PubMed  Google Scholar 

  41. Jedlicka P, Gutierrez-Hartmann A. Ets transcription factors in intestinal morphogenesis, homeostasis and disease. Histol Histopathol. 2008;23:1417–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature. 2012;487:114–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Peng C, Zeng W, Su J, Kuang Y, He Y, Zhao S, et al. Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway. Oncogene. 2016;35:1170–9.

    Article  CAS  PubMed  Google Scholar 

  44. McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C, et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016;126:639–52.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chen J, Fu Y, Day DS, Sun Y, Wang S, Liang X, et al. VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. Nat Commun. 2017;8:383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gollavilli PN, Pawar A, Wilder-Romans K, Natesan R, Engelke CG, Dommeti VL, et al. EWS/ETS-driven Ewing sarcoma requires BET bromodomain proteins. Cancer Res. 2018;78:4760–73.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81974060, 81874177, 81672517, 31771545, and 91749120), the National High Technology Research and Development Program of China (863 Program) (Grant No. 2014AA020801), the National Key R&D Program of China (2019YFC1316002), The Program for Professor of Special Appointment (Young Eastern Scholar) at Shanghai Institutions of Higher Learning (to C-YL), Shanghai Pujiang Program (18PJ1407400), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171918), Innovative research team of high-level local universities in Shanghai and the Innovation Program for Ph.D. students in Shanghai Jiao Tong University School of Medicine (BXJ201827).

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  1. These authors contributed equally: Zhehui Zhu, Jinglue Song, Yuegui Guo

Authors and Affiliations

  1. Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China

    Zhehui Zhu, Jinglue Song, Yuegui Guo, Yuhan Wang, Weijun Ou, Chen-Ying Liu & Long Cui

  2. Shanghai Colorectal Cancer Research Center, 200092, Shanghai, China

    Zhehui Zhu, Zhenyu Huang, Xiaojian Chen, Xuening Dang, Yuji Huang, Chen-Ying Liu & Long Cui

  3. Suzhou Institute of Systems Medicine, Center for Systems Medicine Research, Chinese Academy of Medical Sciences, 215123, Suzhou, Jiangsu, China

    Yili Yang

  4. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, 200438, Shanghai, China

    Wei Yu

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Contributions

LC, C-YL, YY and WY designed the study. ZZ and JS wrote the manuscript. ZZ, ZH, JS and YG performed the experiments. ZZ and YG performed bioinformatics analysis. XC and XD established the animal models. YH, YW and WO were responsible for the data analysis. All of the authors approved this paper.

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Correspondence to Wei Yu, Chen-Ying Liu or Long Cui.

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Zhu, Z., Song, J., Guo, Y. et al. LAMB3 promotes tumour progression through the AKT–FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer. Oncogene 39, 4666–4680 (2020). https://doi.org/10.1038/s41388-020-1321-5

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