Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines

被引：10

作者：

Hosoi, Hiroki ^{[1
,2
]}

Niibori-Nambu, Akiko ^{[1
,3
]}

Nah, Giselle Sek Suan ^{[1
]}

Bahirvani, Avinash Govind ^{[1
]}

Mok, Michelle Meng Huang ^{[1
]}

Sanda, Takaomi ^{[1
,4
]}

Kumar, Alan Prem ^{[1
,5
,6
]}

Tenen, Daniel G. ^{[1
,7
]}

Ito, Yoshiaki ^{[1
]}

Sonoki, Takashi ^{[2
]}

Osato, Motomi ^{[1
,8
,9
]}

机构：

[1] Natl Univ Singapore, Canc Sci Inst Singapore, 14 Med Dr, Singapore 117599, Singapore

[2] Wakayama Med Univ, Dept Hematol Oncol, Kimiidera 811-1, Wakayama 6418510, Japan

[3] Kumamoto Univ, Inst Life Sci, Grad Sch Med Sci, Dept Tumor Genet & Biol, Kumamoto, Japan

[4] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore

[6] Natl Univ Singapore, Yong Loo Lin Sch Med, Canc Translat Res Programme, Singapore, Singapore

[7] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA

[8] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore

[9] Kumamoto Univ, Int Res Ctr Med Sci, Kumamoto, Japan

来源：

GENE | 2021年 / 774卷

基金：

英国医学研究理事会; 新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

RUNX3; Super-enhancer; Epstein-Barr virus; JQ1; MYC; EPSTEIN-BARR-VIRUS; BINDING; MYC; DISRUPTION; EXPRESSION; INHIBITOR; ONCOGENES; LEUKEMIA; FAMILY; CANCER;

D O I：

10.1016/j.gene.2021.145421

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Epstein-Barr virus nuclear antigens 2 (EBNA2) mediated super-enhancers, defined by in silico data, localize near genes associated with B cell transcription factors including RUNX3. However, the biological function of superenhancer for RUNX3 gene (seR3) remains unclear. Here, we show that two seR3s, tandemly-located at 59and 70-kb upstream of RUNX3 transcription start site, named seR3 -59h and seR3 -70h, are required for RUNX3 expression and cell proliferation in Epstein-Barr virus (EBV)-positive malignant B cells. A BET bromodomain inhibitor, JQ1, potently suppressed EBV-positive B cell growth through the reduction of RUNX3 and MYC expression. Excision of either or both seR3s by employing CRISPR/Cas9 system resulted in the decrease in RUNX3 expression and the subsequent suppression of cell proliferation and colony forming capability. The expression of MYC was also reduced when seR3s were deleted, probably due to the loss of trans effect of seR3s on the super-enhancers for MYC. These findings suggest that seR3s play a pivotal role in expression and biological function of both RUNX3 and MYC. seR3s would serve as a potential therapeutic target in EBV-related widespread tumors.

引用

页数：10

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