LAMB3 promotes tumour progression through the AKT-FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer
LAMB3 promotes tumour progression through the AKT-FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer
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LAMB3 通过 AKT-FOXO3/4 轴促进肿瘤进展，并在结直肠癌中受到 BRD2/乙酰化 ELK4 复合物的转录调节
DOI：
10.1038/s41388-020-1321-5
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发表时间：
2020-05-12
期刊：
影响因子：
8
通讯作者：
Cui, Long
中科院分区：
文献类型：
--
作者：
Zhu, Zhehui;Song, Jinglue;Cui, Long
层粘连蛋白-332的异常表达促进多种肿瘤的生长和转移。然而，编码层粘连蛋白-332β3亚单位的LAMB3的异常表达及其作用机制，以及在结直肠癌中异常表达的机制仍不清楚。在这里，我们发现LAMB3在结直肠癌中高表达，并且这种高表达与肿瘤转移和预后不良有关。过表达的LAMB3在体外促进细胞的增殖和迁移，在体内促进肿瘤的生长和转移，而敲除LAMB3则产生相反的作用。LAMB3通过激活大肠癌AKT抑制FOXO_3/4的抑瘤作用。BET抑制剂JQ1和MEK抑制剂U0126均可降低多个结直肠癌细胞LAMB3的mRNA水平。在机制上，ELK4与BRD2通过直接结合LAMB3启动子中的ETS结合基序来调节LAMB3在结直肠癌中的转录。ELK4在K125处发生乙酰化，增强了ELK4与BRD2的相互作用。JQ1阻断了ELK4和BRD2之间的相互作用，导致BRD2与LAMB3启动子的结合减少，LAMB3转录下调。ELK4和BRD2的表达与LAMB3的表达密切相关。LAMB3在结直肠癌中的表达与FOXO_3/4呈负相关。我们的研究揭示了LAMB3通过AKT-FOX03/4轴的促肿瘤作用以及LAMB3在结直肠癌中的转录机制，表明LAMB3是一个潜在的治疗靶点，可以作为BET抑制剂和MEK抑制剂的靶点。
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 beta 3 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.