BRD4 promotes metastatic potential in oral squamous cell carcinoma through the epigenetic regulation of the MMP2 gene
BRD4 promotes metastatic potential in oral squamous cell carcinoma through the epigenetic regulation of the MMP2 gene
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DOI：
10.1038/s41416-020-0907-6
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发表时间：
2020-06
影响因子：
8.8
通讯作者：
Tatsuro Yamamoto;A. Hirosue;Masafumi Nakamoto;R. Yoshida;J. Sakata;Y. Matsuoka;K. Kawahara;Yuka Nagao;M. Nagata;Nozomu Takahashi;A. Hiraki;M. Shinohara;M. Nakao;N. Saitoh;H. Nakayama
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文献类型：
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作者：
Tatsuro Yamamoto;A. Hirosue;Masafumi Nakamoto;R. Yoshida;J. Sakata;Y. Matsuoka;K. Kawahara;Yuka Nagao;M. Nagata;Nozomu Takahashi;A. Hiraki;M. Shinohara;M. Nakao;N. Saitoh;H. Nakayama
口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）的发病率不断增加，其高转移潜能影响患者的生存.含溴结构域4（BRD4）是与乙酰化组蛋白赖氨酸缔合并促进转录的染色质蛋白。BRD4与几种类型癌症的细胞增殖、转移和预后有关。结果BRD 4抑制剂JQ 1能抑制OSCC细胞的增殖、迁移和侵袭，并能抑制OSCC细胞的增殖、迁移和侵袭。JQ1可降低包括基质金属肽酶2（MMP 2）在内的15种转移基因的表达水平。我们的染色质免疫沉淀试验表明，JQ1减少BRD4结合组蛋白H3赖氨酸27乙酰化富集位点在MMP 2基因座。结论BRD 4通过对MMP 2基因的表观遗传调控参与了口腔鳞癌的转移，BRD 4可能成为口腔鳞癌的治疗靶点和转移的预测指标。
BackgroundOral squamous cell carcinoma (OSCC) has increased morbidity, and its high metastatic potential affects patient survival. Bromodomain containing 4 (BRD4) is a chromatin protein that associates with acetylated histone lysines and facilitates transcription. BRD4 has been implicated in cell proliferation, metastasis, and prognosis in several types of cancer. However, the role of BRD4 in OSCC remains to be elucidated.MethodsWe investigated the role of BRD4 and its potential utility as a therapeutic target in OSCC.ResultsJQ1, the BRD4 inhibitor, suppressed the cell proliferation, migration, and invasion in the OSCC cell lines and in vivo. JQ1 reduced the expression levels of 15 metastasis genes in OSCC, includingmatrix metallopeptidase 2(MMP2). Our chromatin immunoprecipitation assay showed that JQ1 reduced the BRD4 binding to the histone H3 lysine 27 acetylation-enriched sites in theMMP2locus. Analyses of biopsy specimens from OSCC patients revealed that theBRD4andMMP2expression levels were correlated in the cancerous regions, and both were highly expressed in lymph node metastasis cases, including delayed metastasis.ConclusionsBRD4 contributes to metastasis in OSCC, through the epigenetic regulation of theMMP2gene, and thus BRD4 may represent a therapeutic target and a novel prediction indicator for metastasis.