BRD4 promotes metastatic potential in oral squamous cell carcinoma through the epigenetic regulation of the MMP2 gene

Tatsuro Yamamoto,Akiyuki Hirosue,Noriko Saitoh,Yuichiro Matsuoka,Akimitsu Hiraki,Masafumi Nakamoto,Hideki Nakayama,Junki Sakata,Nozomu Takahashi,Masanori Shinohara,Masashi Nagata,Kenta Kawahara,Ryoji Yoshida,Yuka Nagao,Mitsuyoshi Nakao

doi:10.1038/s41416-020-0907-6

Tatsuro Yamamoto, Akiyuki Hirosue + Show 13 more

Open Access

https://doi.org/10.1038/s41416-020-0907-6

Copy DOI

Abstract

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, including matrix metallopeptidase 2 (MMP2). Our chromatin immunoprecipitation assay showed that JQ1 reduced the BRD4 binding to the histone H3 lysine 27 acetylation-enriched sites in the MMP2 locus. Analyses of biopsy specimens from OSCC patients revealed that the BRD4 and MMP2 expression 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 the MMP2 gene, and thus BRD4 may represent a therapeutic target and a novel prediction indicator for metastasis.

Highlights

Oral squamous cell carcinoma (OSCC) has increased morbidity, and its high metastatic potential affects patient survival
1234567890();,: In this study, we show that JQ1 suppressed the proliferation and invasion of OSCC cell lines and suppressed the Bromodomain containing 4 (BRD4)-mediated transcriptional activation of a gene involved in metastasis, matrix metallopeptidase 2 (MMP2)
bromodomain and extra-terminal (BET) inhibitor JQ1 suppressed OSCC cell proliferation To investigate the effect of JQ1 on the proliferation of OSCC cells, we treated the two cell lines, HOC313 and SAS, with JQ1

Summary

Introduction

Oral squamous cell carcinoma (OSCC) has increased morbidity, and its high metastatic potential affects patient survival. Oral squamous cell carcinoma (OSCC) is a major head and neck cancer and has negative effects on the quality of life and survival of patients.[1] new diagnosis and therapeutic modalities have been developed, morbidity has tended to increase, and 5year survival rates of 60–65% of the patients have not significantly improved over the past 30 years.[1,2] A subpopulation of OSCC has high malignant potential and includes strongly invasive types and metastatic cases with a poor prognosis.[3] To improve these patient outcomes, it is important to identify novel biomarkers for the diagnosis of metastasis and the elucidation of therapeutic targets in OSCC.

Methods

Results

Conclusion