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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

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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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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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 or 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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